Characterisation of nuclear envelope proteins across the human lifespan and their role in modulating fibrosis in cardiac and skin fibroblasts.

Page 1

ASTAR and King’s College London PhD Studentships October 2026 Entry

Page 2

Contents

THEME1: Cells, Molecules and the Basis of Health and Disease................................ ...................... 3 1.1 Characterisation of nuclear envelope proteins across the human lifespan and their role in modulating fibrosis in cardiac and skin fibroblasts. ............................................................................ 4 2.1 Comparative Analysis of Bacterial Determinants Contributing to Persistent Infections in the Zebrafish Model. ................................................................................................................................. 6 3.1 Decoding human ageing through alternative splicing and transcriptional dysregulation. ........... 8 4.1 Dissecting drivers of ageing by digital fingerprinting of tissue regeneration using spatial transcriptomics and live cell imaging. ............................................................................................... 10 5.1 Effects of ultra-processed foods on oral microbiome. ............................................................... 12 6.1 Noncanonical target discovery for future development of T cell-mediated immunotherapy against cancer. .................................................................................................................................. 14 7.1 Palindromic ligands to target lumazine synthase in the treatment of tuberculosis................... 16 8.1 Prompt-Based AI for Single-Cell Multi-omics: Decoding Cellular Mechanisms in Cancer. ......... 18 9.1 Unravelling epigenetic mechanisms of vascular smooth muscle cell ageing and calcification. . 20 10.1 Whole exome sequencing in glaucoma scarring and blindness. .............................................. 22 THEME2: Neuroscience and Mental Health ................................ ................................ ................. 24 1.2 A comprehensive investigation of the role of mitochondrial variation in Amyotrophic Lateral Sclerosis utilising large scale genomics and stem cell models. ......................................................... 25 2.2 Childhood trajectories of white matter connectivity and mental health: insights across geographical contexts. ...................................................................................................................... 27 2.2 Excitation-Inhibition balance and imbalance in typical and atypical development. .................. 29 4.2 From mastication to mind: impact of oral processing on the effects of dietary flavonoids on mood, cognition and mental health. ................................................................................................ 31 5.2 Integrating neuroimaging and omics to unravel the link between early life stress and childhood depression. ........................................................................................................................................ 33 6.2 RNA sensing devices to study dynamics of non-coding RNAs in neurodegeneration. ............... 35

Page 3

ASTAR and King’s College London PhD Studentships

When choosing a project from this catalogue in the funding section & research proposal section of the online application form, please enter the funding code that corresponds to the theme of your first project choice:

1. Cells, Molecules and the Basis of Health and Disease: THEME12026 2. Neuroscience and Mental Health: THEME22026

Important dates:

Date Application Stage

Deadline for application Sunday, 22 February 2026, 23:59 UK Time

Application Outcome By 20 March 2026

Interviews Week commencing 13 April 2026

Interview Outcomes By 17 April 2026

Acceptance of studentship offer By 01 Mayl 2026

Degree Start Date October 2026

The 2026/27 studentships will commence in October 2026. For further information or queries relating to the application process, please contact: doctoralstudies@kcl.ac.uk. Projects listed in this catalogue are subject to amendments, candidates invited to interview will have the opportunity to discuss projects in further detail.

Page 4

THEME1: Cells, Molecules and the Basis of Health and Disease

Page 5

1.1 Characterisation of nuclear envelope proteins across the human lifespan and their role in modulating fibrosis in cardiac and skin fibroblasts. Co-Supervisor King’s: Dr Matthew Stroud Faculty: Faculty of Life Sciences & Medicine E-mail: matthew.stroud@kcl.ac.uk Website: http://www.stroudlab.com

Co-Supervisor ASTAR: Dr Yin Loon Lee Research Institute: ASTAR Skin Research Labs Email: yinloonlee@a-star.edu.sg Website: https://www.a-star.edu.sg/asrl/group-leaders/dr-lee-yin-loon

Project Description

The extracellular matrix (ECM) forms a network of fibres between cells in solid organs. Modulation of ECM deposition is essential both for proper heart development, but also after harmful insults such as a heart attack. Elevated ECM deposition in the heart can result in excessive scarring that is detrimental for normal function, such as during ageing, or after a heart attack. In contrast, loss of ECM production is associated with skin aging. Signalling pathways are known to regulate ECM deposition but many details remain unclear, in particular, the role of the nuclear envelope. The nuclear envelope sits at the interface between the genome and the cell skeleton. One group of proteins lining the nuclear envelope and interacting with the force - transmitting cell skeleton are the Linker of Nucleoskeleton and Cytoskeleton complexes. The LEM domain class of nuclear envelope proteins play roles in mechanically stabilizing the nuclear envelope. Both these classes of nuclear envelope proteins regulate signalling pathwa ys that determine scar formation or fibrosis in tissue, though the precise details of how this occurs is unclear. The overarching goals of this PhD are to uncover the mechanisms by which the nuclear envelope modulates fibrosis in cells and tissue systems.

Year 1: Screenings to identify nuclear envelope factors that regulate scarring in both heart and skin. Year 2/3: Validation of screening hits and protein-protein interactions in cells. Year 3/4: Cell biology and in vivo validation of putative protein interactors and screening hits. Thesis writing (3m).

Page 6

Representative publication from supervisors: Ross JA…Stroud MJ$ . Lem2 is essential for cardiac development by maintaining nuclear integrity. Cardiovasc Res. 2023. doi: 10.1093/cvr/cvad061.

Leong EL… Lee YL. Nesprin-1 LINC complexes recruit microtubule cytoskeleton proteins and drive pathology in Lmna-mutant striated muscle. Hum Mol Genet. 2023 Jan 6;32(2):177-191. doi: 10.1093/hmg/ddac179.

Page 7

2.1 Comparative Analysis of Bacterial Determinants Contributing to Persistent Infections in the Zebrafish Model. Co-Supervisor King’s: Dr Vincenzo Torraca Faculty: Faculty of Life Sciences & Medicine E-mail: vincenzo.torraca@kcl.ac.uk Website: https://www.kcl.ac.uk/people/vincenzo-torraca

Co-Supervisor ASTAR: Dr Stefan Oehlers Research Institute: ASTAR Infectious Diseases Labs Email: stefanoehlers@a-star.edu.sg Website: https://www.a-star.edu.sg/idlabs/people/our-investigators/stefan-oehlers

Project Description

This PhD project explores how certain bacteria evade the immune system and establish long -lasting infections. The project will focus on two prototypical bacteria that are known to establish persistent infections: Shigella sonnei, an important diarrhoeal pathogen, and Mycobacterium marinum, a close relative of the bacterium that causes tuberculosis. The project will take advantage of the zebrafish as a model organism, which allows to directly observe infection and immune responses, thanks to the transparency in early life stages. The project will provide the student with training in advanced molecular biology and microbiology techniques, including live imaging, gene editing (i.e., CRISPR/Cas9), bacterial genetics, and bioinformatics for data analysis. This tr aining will equip the student with a wide -ranging skill set applicable across infection biology and immunology research. Our overarching objective is to reveal how bacteria persist within the host and evade immune defences, especially focusing on the role of certain immune cells (i.e., macrophages) as potential hiding spots for persistent bacteria and certain immune signalling molecules (i.e., interferons) as potential systems to control persistent infections. The findings from this research may guide the development of better treatments for persistent bacterial infections that do not respond to traditional therapies, benefiting public health. This project offers a unique opportunity for a PhD candidate to work internationally and gain diverse research experience.

Representative publication from supervisors: Torraca V, Brokatzky D, Miles SL, Chong CE, De Silva PM, Baker S, Jenkins C, Holt KE, Baker KS, Mostowy S. Shigella serotypes associated with carriage in humans establish persistent infection in zebrafish. J Infect Dis. 2023 Oct 18;228(8):1108-1118. DOI: 10.1093/infdis/jiad326. Co-corresponding author.

Page 8

Wee D, Pandey M, Chen Y, Lorenzini PA, Chow EWL, Wang Y, Singhal A, Oehlers SH (2025). Primary tuberculous mycobacterial granulomas provide a niche for superinfecting Mycobacterium abscessus. Nat Commun. In press. Corresponding author.

Page 9

3.1 Decoding human ageing through alternative splicing and transcriptional dysregulation. Co-Supervisor King’s: Professor Kerrin Small Faculty: Faculty of Life Sciences & Medicine E-mail: kerrin.small@kcl.ac.uk Website: https://www.kcl.ac.uk/people/kerrin-small

Co-Supervisor ASTAR: Dr Jonathan Goke Research Institute: Genome Institute of Singapore Email: jonathangoeke@a-star.edu.sg Website: https://www.a-star.edu.sg/gis/our-people/faculty-staff/members/jonathan-g%C3%B6ke

Project Description

In healthy individuals, each cell uses instructions encoded in our genes to make the molecules it needs to function. These instructions can be read in different ways, producing alternative versions of the same gene. This process is called alternative splicing, and it is essential for healthy cellular function, but it becomes less reliable with age. Mistakes in this process may contribute to ageing itself and may increase the development of age-related diseases.

This PhD project will explore how alternative splicing changes as people age, using a unique study of 200 twins who were followed for 15 years. Using innovative long -read RNA sequencing technology, which can capture the full complexity of gene activity, th e student will examine both known and newly discovered splicing patterns, obtained from cutting -edge computational approaches. They will investigate how these patterns differ between individuals, change over time, and relate to health, disease and genetics.

The project offers comprehensive training in human genetics, computational biology and the latest long-read sequencing analysis methods. The student will gain experience working with large -scale genomic datasets, advanced statistical modelling and integration of molecular data with clinical health records.

• Year 1: Training in genomics and computational analysis, and the study of genetic factors that influence splicing. • Year 2: Apply cutting-edge tools to detect and quantify novel splicing events in long-read data. • Year 3–4: Link molecular changes to ageing and health outcomes.

Page 10

This research aims to understand how cellular ageing contributes to disease and may help identify new ways to support healthier ageing.

Representative publication from supervisors: Chen Y, Davidson N, Wan YK, Yao F, Su Y, Gamaarachchi H, Sim A, Patel H, Low HM, Hendra C, Wratten L, Hakkaart C, Sawyer C, Iakovleva V, Lee PL, Xin L, Ng H, Loo JM, Ong X, Ng HQA, Wang J, Koh WQC, Poon SKP, Stanojevic D, Tran HD, Lim KHE, Toh SY, Ewels PA , Ng HH, Iyer NG, Thiery A, Chng WJ, Chen L, DasGupta R, Sikic M, Chan YS, Tan P, Wan Y, Tam WL, Yu Q, Khor CC, Wüstefeld T, Lezhava A, Pratanwanich PN, Love MI, Goh WSS, Ng SB, Oshlack A, SG -NEx consortium, Göke J+. A systematic benchmark of Nanopore long read RNA sequencing for transcript level analysis in human cell lines. Nature Methods (2025) 22: 801–812.

Brotman SM, El -Sayed Moustafa JS, Guan L, Broadaway KA, Wang D, Jackson AU, Welch R, Currin KW, Tomlinson M, Vadlamudi S, Stringham HM, Roberts AL, Lakka TA, Oravilahti A, Fernandes Silva L, Narisu N, Erdos MR, Yan T, Bonnycastle LL, Raulerson CK, Raza Y, Yan X, Parker SCJ, Kuusisto J, Pajukanta P, Tuomilehto J, Collins FS, Boehnke M, Love MI, Koistinen HA, Laakso M, Mohlke KL, Small KS, Scott LJ. Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regul ation and cardiometabolic traits. Nature Genetics. 2025 Jan;57(1):180-192.

Page 11

4.1 Dissecting drivers of ageing by digital fingerprinting of tissue regeneration using spatial transcriptomics and live cell imaging. Co-Supervisor King’s: Dr Robert Knight Faculty: Faculty of Dentistry, Oral & Craniofacial Sciences E-mail: robert.knight@kcl.ac.uk Website: https://www.kcl.ac.uk/research/knight-group

Co-Supervisor ASTAR: Dr Kok Hao Chen Research Institute: Genome Institute of Singapore Email: chenkh@gis.a-star.edu.sg Website: https://khchenlab.github.io

Project Description

Ageing affects many cells required for tissue homeostasis and repair, resulting in weakness and poor wound healing. Immune cells, including macrophages, show age-associated changes that are thought to affect their ability to support wound healing and tissue repair, but has proven challenging to identify factors affected by ageing that can alter immune cell function. One hypothesis is that a failure of macrophages to undergo resolution from a pro -inflammatory to a pro -regeneration state may be causal for poo r regeneration or repair. Identifying factors affecting macrophage function may offer a route for designing therapies that can promote more effective tissue repair and hence function in ageing.

Objectives for the project include: 1) identifying which genes active in macrophages are affected by ageing, 2) test whether macrophage ageing-affected genes regulate macrophages during tissue repair, 3) whether these genes affect how human macrophages control stem cell responses.

These will be achieved by characterising macrophages during regeneration of zebrafish models of ageing, testing genes active in the macrophages and showing if these are driving ageing-associated behaviours. Cell behaviour will be visualised by fluorescent microscopy and gene activity will be assessed by profiling individual cells and manipulating their function by genetics and using drugs. This will identify molecules which regulate macrophage transition during t issue repair and are affected by ageing. We w ill then evaluate whether these molecules are important for regeneration by manipulating them in a human co-culture system containing macrophages and stem cells.

Page 12

• Year 1 (King’s): Milestone 1: optimise methods to be used for spatial analysis of gene expression in macrophages by FISH. Milestone 2: characterise macrophage molecular profiles during regeneration in zebrafish ageing models. • Year 2 (ASTAR): Milestone 3: analyse single cell sequencing data to identify markers, pathways, signalling events, and putative gene regulatory networks (GRNs) . Milestone 4: perform FISH for measuring gene expression in tissues of zebrafish ageing models. • Year 3 (ASTAR): Milestone 5: define gene expression differences in macrophages during transition to resolution in healthy and aged fish. • Year 3 (King’s): Milestone 6: evaluate candidate age-associated genes by CRISPR/Cas9 mutagenesis and pharmacological methods for functional importance during regeneration. • Year 4 (King’s): Milestone 7: determine whether the selected candidate genes regulate macrophage dependent stem cell function in a human cell co-culture system.

Representative publication from supervisors: Robert Knight (Craniofacial and Regenerative Biology) Yuan, Y., Dyer C., Knight, R. D. Muscle regeneration can be rescued in a telomerase deficient zebrafish model of ageing by MMP inhibition Ageing Cell 2025 Sep 25: e70238 doi:10.1111/acel.70238.

Kok Hao Chen (Spatial and Single-cell transcriptomics) Goh, J. J. L., Chou, N., Seow, W. Y., Ha, N., Cheng, C. P. P., Chang, Y., Zhao, Z. W., Chen, K. H. Highly specific multiplexed RNA imaging in tissues with split-FISH. Nature Methods, (2020) https://doi.org/10.1038/s41592- 020-0858-0.

Page 13

5.1 Effects of ultra-processed foods on oral microbiome. Co-Supervisor King’s: Professor Guy Carpenter Faculty: Faculty of Dentistry, Oral & Craniofacial Sciences E-mail: guy.carpenter@kcl.ac.uk Website: https://www.kcl.ac.uk/people/guy-carpenter

Co-Supervisor ASTAR: Dr Lim Su Hui Research Institute: Singapore Institute of Food and Biotechnology Innovation (SIFBI) Email: limsuhui@a-star.edu.sg Website: https://www.a-star.edu.sg/sifbi

Project Description

The effects of ultra-processed foods on gut bacteria have been shown but for bacteria in the mouth the effect is still being established. Whereas gut bacteria are directly affected (by direct contact) oral bacteria will be affected indirectly via the bloodstream. Both nutrients and chemicals in Ultra Processed Foods are absorbed by the gut, passing into the bloodstream. So, examining a microbiome which relies on plasma -derived nutrients may give us insights into how much of UPF actually reaches the organs (brain, he art etc.) which is something we don’t currently know.

• Year 1 (London): Collect saliva samples from 50 participants with dietary information. Use in vitro culture methods to assess impacts of nitrates/ nitrosamines on cultures of oral microbiome. • Year 2 (Singapore): Collect saliva samples from 50 participants. Determine levels of salivary nitrate, oral metabolome and microbiome composition (as previously) in both populations. • Year 3 (Singapore): Perform intervention study increasing dietary levels of processed meats, reassess effects on oral microbiome. • Year 4 (London): Perform intervention study on UK population.

Representative publication from supervisors: Guy Carpenter: Zhang, S., Clasen, F., Cai, H. & Carpenter G.H . Nitrate supplementation affects taste by changing the oral metabolome and microbiome. npj Biofilms Microbiomes 11, 69 (2025). https://doi.org/10.1038/s41522-025-00689-8.

Ng Siew Bee: Po-Hsiang Wang, Zann Tan, Choy Eng Nge, Nurhidayah Basri, Lina Xian Yu Lee, Aaron Thong, Mario Wibowo, Elaine Chin, Sharon Carmelita Crasta, Geraldine Chan, Yoganathan Kanagasundaram, Siew

Page 14

Bee Ng. Sustainable biotransformation of microalgae via probiotic fermentation for enhanced functional, nutritional, and sensory properties. Sustainable Food Technol., 2025. https://doi.org/10.1039/D5FB00492F.

Lim Su Hui: Lim, S. H., Yong, G. J. M., Chia, C. Y., Man, S. M., Subramanian, G. S., Oh, G., Cheong, E. J. Y., & Kiryukhin, M. v. (2024). Mucin coated protein -polyphenol microcarriers for daidzein delivery. Food and Function, 15(5), 2645–2654. https://doi.org/10.1039/d3fo03356b.

Page 15

6.1 Noncanonical target discovery for future development of T cell -mediated immunotherapy against cancer. Co-Supervisor King’s: Professor Michele Mishto Faculty: Faculty of Life Sciences & Medicine E-mail: michele.mishto@kcl.ac.uk Website: https://www.kcl.ac.uk/people/michele-mishto

Co-Supervisor ASTAR: Dr Olaf Roetzschke Research Institute: Singapore Immunology Network Email: OlafRotzschke@a-star.edu.sg Website: https://www.a-star.edu.sg/sign/people/principal-investigators/olaf-r%C3%B6tzschke

Project Description

Recent research has shown that noncanonical epitopes, which include both cryptic epitopes and proteasome- generated spliced epitopes, represent a sizeable portion of the full set of antigenic peptides presented by cancer cells to lymphocytes. Few labs have attempted the development of novel immunotherapies against cancer targeting these non-canonical epitopes.

The overall objective of this project is to investigate the mechanisms of presentation of canonical and non - canonical epitopes in few selected cancers and how they can activate an immune response to eliminate cancer cells. The student will work with the Mi shto and Rotzschke labs and their international colleagues in a multi-disciplinary project that requires the training and application of techniques such as: • RNA sequencing • Mass spectrometry and proteomics • Flow cytometry • Mass flow cytometry • Molecular and cellular immunology (ELISA, ELISpot, etc.) • Primary and cell line cultures • Plasmid and viral vector cloning, transduction, transformation and transfection • PCR, RT-PCR, qRT-PCR • Potentially in vivo experiments on lymph node model • Basic and more advanced usage of in-house generated software (Python, C+) • Statistical analysis

Page 16

• Multi-omics analysis and gene enrichment analysis

Representative publication from supervisors: Soh WT, Roetschke HP, Cormican JA, Teo BF, Chiam NC, Raabe M, Pflanz R, Henneberg F, Becker S, Chari A, Liu H, Urlaub H, Liepe J, Mishto M. Degradation of proteins by human 20S proteasomes sheds light on the interplay between peptide hydrolysis and peptide splicing. Nat. Comm. 2024 Feb 7;15(1):1147. doi: 10.1038/s41467-024-45339-3.

Lim J, Puan KJ, Wang LW, Teng KWW, Loh CY, Tan KP, Carissimo G, Chan YH, Poh CM, Lee CY, Fong SW, Yeo NK, Chee RS, Amrun SN, Chang ZW, Tay MZ, Torres -Ruesta A, Leo Fernandez N, How W, Andiappan AK, Lee W, Duan K, Tan SY, Yan G, Kalimuddin S, Lye DC, Leo YS, Ong SWX, Young BE, Renia L, Ng LFP, Lee B, Rötzschke O. Data -Driven Analysis of COVID -19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals. Front Immunol. 2021 Nov 19;12:710217. doi: 10.3389/fimmu.2021.710217. PMID: 34867943; PMCID: PMC8640498.

Lim J. Destabilizing single chain major histocompatibility complex class I protein for repurposed enterokinase proteolysis. Sci Rep. 2020 Sep 10;10(1):14897. doi: 10.1038/s41598-020-71785-2. PMID: 32913247; PMCID: PMC7483518.

Page 17

7.1 Palindromic ligands to target lumazine synthase in the treatment of tuberculosis. Co-Supervisor King’s: Professor André Cobb Faculty: Faculty of Natural, Mathematical & Engineering Sciences E-mail: andre.cobb@kcl.ac.uk Website: https://www.kcl.ac.uk/people/andre-cobb

Co-Supervisor ASTAR: Dr Amit Singhal Research Institute: ASTAR Infectious Diseases Labs Email: AmitSinghal@a-star.edu.sg Website: https://www.a-star.edu.sg/idlabs/people/our-investigators/amit-singhal

Project Description

The number of fatalities associated with tuberculosis in 2024 was 1.23 million; a major proportion related to drug resistant bacteria. Parallel to this, antimicrobial resistance (AMR) is estimated to cause at least 700000 deaths a year globally over all; a figure that is predicted to rise to 10 million by 2050 if no action is taken. To address this, it is essential to investigate untapped therapeutic targets. This project seeks to address one such protein known as “lumazine synthase”, which occurs in bacteria, but not humans, making it a promising drug target. It is essential to the bacterium, without which it will die. This protein has a high degree of symmetry, as it is made of five identical units that cluster together to form a pentagon. We have previously shown that we can exploit this symmetry to render such a protein inactive by dimerising these pentagons using symmetric ligands. We will explore the potential for this technology to be applied to lumazine synthase. All compounds made will be examined for binding at KCL and tested microbiologically at ASTAR.

• Year 1: Objectives: (1) Make ligands based on literature/computational assessment (2) Protein synthesis/cocrystallisations. Skills: Synthesis, NMR, XRD, DFT, ITC, protein production/purification. • Year 2: Objectives: (1) Expand library; build understanding of monomeric vs dimeric binding. Skills: As above and Mass Spectroscopy. • Year 3: Objectives: Biological testing at ASTAR. Skills: Microbiology and tissue culture. • Year 4: Objectives: (1) Finalise biological data and analyse data compared to binding and crystallographic data (2) Write thesis/remaining publications. Skills: As above and comparative data analysis.

Page 18

Representative publication from supervisors: COBB: Kondacs, L.; Parijat, P.; Cobb, A. J. A.; Kampourakis, T. Synthesis and Biophysical Characterization of Fingolimod Derivatives as Cardiac Troponin Antagonists. ACS Med. Chem. Lett. 2024, 15, 413. (Co - corresponding author).

STEINER : Atherton J.; Chegkazi, M. S.; Leusciatti, M.; Di Palma, M.; Peirano, E.; Pozzer, L. S.; Meli, M. V. A.; Pasqualato, S.; Foran, T.; Morra, G. ; Steiner, R. A. Microtubule association induces a Mgfree apo -like ADP pre-release conformation in kinesin-1 that is unaffected by its autoinhibitory tail. Nat Commun. 2025, 16(1), 6214. (Co- corresponding author).

SINGHA: Del Rosario R. C. H.; Poschmann, J.; Lim, C.; Cheng, C. Y.; Kumar, P.; Riou, C.; Ong, S.T.; Gerges, S.; Hajan, H. S.; Kumar, D.; Marzuki, M.; Lu, X.; Lee, A.; Wijaya, G. C.; Rayan, N. A.; Zhuang, Z.; Du Bruyn, E.; Chee, C. B. E.; Lee, B.; Lum, J.; Zolezzi, F.; Poidinger, M.; Rotzschke, O.; Khor, C. C.; Wilkinson, R. J.; Wang, Y. T.; Chandy, G. K.; De Libero, G.; Singhal, A.; Prabhakar, S. Histone acetylome -wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection. Nat Microbiol. 2022, 7(2), 312. (Co- corresponding author).

Page 19

8.1 Prompt-Based AI for Single -Cell Multi-omics: Decoding Cellular Mechanisms in Cancer. Co-Supervisor King’s: Dr Mohammad Mahdi Karimi Faculty: Faculty of Life Sciences & Medicine E-mail: mohammad.karimi@kcl.ac.uk Website: https://www.kcl.ac.uk/people/mohammad-mahdi-karimi

Co-Supervisor ASTAR: Dr Yao Yinghua Research Institute: ASTAR Centre for Frontier AI Research (ASTAR CFAR) Email: YaoYinghua@a-star.edu.sg Website: https://www.a-star.edu.sg/cfar/about-cfar/our-team/yao-yinghua

Co-Supervisor ASTAR: Dr Pan Yuangang Research Institute: ASTAR Centre for Frontier AI Research (ASTAR CFAR) Email: PanYuangang@a-star.edu.sg Website: https://www.a-star.edu.sg/cfar/about-cfar/our-team/dr-pan-yuangang

Co-Supervisor ASTAR: Professor Ivor Tsang Research Institute: ASTAR Centre for Frontier AI Research (ASTAR CFAR) Email: IvorTsang@a-star.edu.sg Website: https://www.a-star.edu.sg/cfar/about-cfar/management/prof-ivor-tsang

Project Description

Cancer contains many different types of cells including malignant cells, immune cells, and supportive stromal cells that interact in complex ways. Understanding these interactions is essential for improving treatments. New technologies now allow researchers to measure thousands of molecules in individual cells, but analysing this information requires advanced computational skills. This project will build an artificial intelligence system that allows cancer researchers to analyse single -cell data simply by typing clear instructions in everyday language. The system will be developed jointly by King’s College London and ASTAR CFAR in Singapore. Once built, it will be used to study how cells behave in different cancers, how tumours respond to therapy, and how treatment-resistant cells emerge. The student will receive training in cancer biology, computational analysis, and AI-assisted methods.

Page 20

• Year 1: focuses on learning and initial tool development. • Years 2 –3 at ASTAR CFAR : focus on building the AI components and applying them to tumour datasets. • Year 4: focuses on publications and thesis writing

Representative publication from supervisors: Dr Mohammad M. Karimi (King’s College London) Karimi, M.M., Guo, Y., Cui, X. et al. The order and logic of CD4 versus CD8 lineage choice and differentiation in mouse thymus. Nat Commun 12, 99 (2021). https://doi.org/10.1038/s41467- 020-20306-w.

Dr Pan Yuangang (ASTAR CFAR) Fang Y, Li X, Pan Y, Huang X, Tsang IW. Boosting with Fewer Tokens: Multi- Query Optimization for LLMs Using Node Text and Neighbor Cues. In 2025 IEEE 41st International Conference on Data Engineering (ICDE) 2025 May 19 (pp. 2684-2697).

Dr Yao Yinghua (ASTAR CFAR) Yao Y, Pan Y, Chen X. Generative co -design of antibody sequences and structures via black -box guidance in a shared latent space. Proceedings of the 34rd International Joint Conference on Artificial Intelligence (2025).

Prof Ivor Tsang (ASTAR CFAR) Bowen Xing, Ivor W. Tsang. HC^2L: Hybrid and Cooperative Contrastive Learning for CrossLingual Spoken Language Understanding. IEEE Trans. Pattern Anal. Mach. Intell. 46(12): 8094- 8105 (2024).

Page 21

9.1 Unravelling epigenetic mechanisms of vascular smooth muscle cell ageing and calcification. Co-Supervisor King’s: Professor Catherine Shanahan Faculty: Faculty of Life Sciences & Medicine E-mail: cathy.shanahan@kcl.ac.uk Website: https://kclpure.kcl.ac.uk/portal/en/persons/cathy.shanahan/

Co-Supervisor ASTAR: Roger Foo Research Institute: Institute of Molecular and Cell Biology Email: mdcrfsy@nus.edu.sg Website: https://www.a-star.edu.sg/imcb

Project Description

Vascular calcification is the deposition of apatite mineral in the vessel wall and is a well-established risk factor for cardiovascular morbidity and mortality. It is associated with vascular stiffening as well as rupture of atherosclerotic plaques and heart attacks. Vascular calcification is highly prevalent in the ageing population and accelerated in diabetes and chronic kidney disease. It is mediated by vascular smooth muscle cells (VSMCs) which undergo osteogenic differentiation as the cells age and approach senescence and these cells modify the extracellular matrix and orchestrate calcification. Despite the current state of knowledge there are no treatment options. This project seeks to understand how cells change their genetic characteristics as they age leading to this bone -like phenotype. Using animal and human in vitro models of ageing and calcification combined with epigenetic and transcriptomic techniques we aim to identify the key transcription factors that change the genetic landscape during ageing and promote osteogenic change. We will also test in these models whether interfering with these pathways can alleviate some of the cellular changes driving vascular ageing. Understanding whether cells from different developmental origins age at dif ferent rates and by different mechanisms will potentially lead to the identification of novel therapeutic targets for the treatment of this detrimental and prevalent pathology.

• Year 1: Completion of the single cell and ATAC sequencing for the different timepoints of the mouse ageing and calcification model. • Year 2: Completion of bioinformatic analysis and verification of mouse mechanisms and pathways in human primary cell models of VSMC ageing.

Page 22

• Year 3: Production and SMC differentiation of iPSCs into different developmental origins and transcriptomic analysis. • Year 4: Complete data analysis, manuscript and thesis preparation.

Representative publication from supervisors: Mineral Stress Drives Loss of Heterochromatin: An Early Harbinger of Vascular Inflammaging and Calcification. Ho CY, Wu MY, Thammaphet J, Ahmad S, Ho C S J, Draganova L, Anderson G, Jonnalagadda US, Hayward R, Shroff R, Wen WTL, Verhulst A, Foo RS, Shanahan CM. Circ Res. 2025 Feb 14;136(4):379-399. doi: 10.1161/CIRCRESAHA.124.325374.

Transcriptional regulation in heart development, disease and regeneration: reassessing the fetal gene hypothesis. Porrello ER, Lee CJM, Foo RSY, Elliott DA. Nat Rev Cardiol. 2025 Sep 5. doi: 10.1038/s41569-025- 01205-3.

Page 23

10.1 Whole exome sequencing in glaucoma scarring and blindness. Co-Supervisor King’s: Dr Cynthia Yu Wai Man Faculty: Faculty of Life Sciences & Medicine E-mail: cynthia.yu-wai-man@kcl.ac.uk Website: https://www.kcl.ac.uk/people/cynthia-yu-wai-man

Co-Supervisor ASTAR: Dr Khor Chiea Chuen Research Institute: Genome Institute of Singapore Email: khorcc@a-star.edu.sg Website: https://www.a-star.edu.sg/gis/our-people/faculty-staff/members/chiea-chuen-khor

Project Description

Glaucoma blinds millions of people worldwide and scarring is the main reason why surgery in glaucoma stops working. At present, we have no ways of predicting how badly a patient will scar after glaucoma surgery. Our aim is to stratify the individual risk of scarring in glaucoma patients. We will use modern gene techniques to compare the genetic fingerprint in the blood samples of a well-characterised group of 300 patients who had glaucoma surgery. We will compare two groups of patients. One group (125 patients) represents the ‘bad scarrers’ who had early failure after surgery, while the other group (175 patients) represents the ‘non - scarrers’ with long-term success after surgery.

We can do this work because we have access to over 3000 stored blood and tissue samples of glaucoma surgery patients with detailed clinical information in the UK (UK Glaucoma BioResource), as well as a reference set of over 6000 patients worldwide from different ethnic groups. These unique resources will allow detailed analyses across different ethnicities and groups.

Currently, doctors rely mostly on their personal experience and a trial -and-error strategy to determine the most effective anti-scarring treatment in their patients. This research will directly improve the management of glaucoma patients as it will enable us to predict the risk of scarring and to tailor the anti-scarring treatment regimen in each patient. Being able to stratify the risk of scarring will be a clinically useful and cost -saving tool to prevent undertreating or exposing glaucoma patients to unnecessary treatments with side effects.

Page 24

Representative publication from supervisors: Yu-Wai-Man C , Tagalakis AD, Meng J, Bouremel Y, Lee RMH, Virasami A, Hart SL, Khaw PT. Genotype - phenotype associations of IL -6 and PRG4 with conjunctival fibrosis after glaucoma surgery. JAMA Ophthalmol. 2017 Nov;135(11):1147-55.

Genetics of Exfoliation Syndrome Partnership, Li Z, Wang Z, Lee MC, Zenkel M, Peh E, Ozaki M, Topouzis F, Nakano S, Chan A, Chen S, Williams SEI, Orr A, Nakano M, Kobakhidze N, Zarnowski T, Popa-Cherecheanu A, Mizoguchi T, Manabe SI, Hayashi K, Kazama S, Inoue K, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Ideta R, Ishiko S, Yoshida A, Tokumo K, Kiuchi Y, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Aihara M, Inatani M, Mori K, Ikeda Y, Ueno M, Gaston D, Rafuse P, Shuba L, Saunders J, Nicolela M, Ch ichua G, Tabagari S, Founti P, Sim KS, Meah WY, Soo HM, Chen XY, Chatzikyriakidou A, Keskini C, Pappas T, Anastasopoulos E, Lambropoulos A, Panagiotou ES, Mikropoulos DG, Kosior-Jarecka E, Cheong A, Li Y, Lukasik U, Nongpiur ME, Husain R, Perera SA, Álvarez L, García M, González-Iglesias H, Cueto AFV, Cueto LFV, Martinón-Torres F, Salas A, Oguz Ç, Tamcelik N, Atalay E, Batu B, Irkec M, Aktas D, Kasim B, Astakhov YS, Astakhov SY, Akopov EL, Giessl A, Mardin C, Hellerbrand C, Cooke Bailey JN, Igo RP Jr, Haines JL, Edward DP, Heegaard S, Davila S, Tan P, Kang JH, Pasquale LR, Kruse FE, Reis A, Carmichael TR, Hauser M, Ramsay M, Mossböck G, Yildirim N, Tashiro K, Konstas AGP, Coca-Prados M, Foo JN, Kinoshita S, Sotozono C, Kubota T, Dubina M, Ritch R, Wiggs JL, Pasutto F, Schlötzer -Schrehardt U, Ho YS, Aung T, Tam WL, & Khor CC. Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye. JAMA. 2021; 325:753-764.

Page 25

THEME2: Neuroscience and Mental Health

Page 26

1.2 A comprehensive investigation of the role of mitochondrial variation in Amyotrophic Lateral Sclerosis utilising large scale genomics and stem cell models. Co-Supervisor King’s: Professor Alfredo Iacoangeli Faculty: Institute of Psychiatry, Psychology & Neuroscience E-mail: alfredo.iacoangeli@kcl.ac.uk Website: https://www.kcl.ac.uk/people/alfredo-iacoangeli

Co-Supervisor ASTAR: Dr Shi-Yan Ng Research Institute: Genome Institute of Singapore Email: NgShiYan@a-star.edu.sg Website: https://www.a-star.edu.sg/gis/our-people/faculty-staff/members/ng-shi-yan

Project Description

1) Background Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive paralysis, leading to death from respiratory failure within 2 -5 years. Mitochondria are essential cellular organelles responsible for regulating a number of key processes, and their malfunctioning is one of the earliest pathophysiological in ALS. Mitochondria possess their own DNA distinct from the nuclear genome, and despite their central role in ALS, efforts in investigating mitochondrial DNA variation in the context of ALS have been very limited.

2) Novelty & Importance This project proposes a novel comprehensive approach to study the role of mitochondrial variants in the pathogenesis of ALS, which has potential to discover new insight into the biological basis of this disease and to highlight new treatment avenues.

3) Aims & Objectives This project aims to elucidate the role of mitochondrial DNA variation in the pathogenesis of ALS. We will achieve this by 1) utilising large -scale genomics datasets of thousands of people with ALS and controls, to identify mitochondrial mutations associat ed with disease risk or distinct clinical outcomes. 2) We will then utilise in -silico methods such as APOGEE, and modelled using molecular dynamics simulations, for the characterisation of their functional effect, and 3) study their mechanism of action in cell models of the disease. Mitochondrial variants will be created in pluripotent stem cell (PSC) lines using the cybrid

Page 27

technology. PSCs will be differentiated into spinal motor neurons, and phenotypic analyses will be carried out by immunostaining and metabolic profiling assays. Aims 1-2 will take place at KCL aim 3 will take place at ASTAR in Singapore.

• Year 1 and Year 2 (KCL): 24 months - will focus on large-scale genomic analyses and will take place at KCL. • Year 3 (ASTAR): 12 months - will take place in Singapore at the Genome Institute of Singapore (ASTAR GIS) • Year 4 (First 6 months at ASTAR and last 6 months at KCL): 12 months - during the final 6 months, the student will return to KCL to complete any remaining analyses, write the thesis, and prepare for submission and viva.

Representative publication from supervisors: Hor, Jin -Hui, et al. "ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation." Cell Death & Differentiation 28.4 (2021): 1379-1397.

Harvey, Calum, et al. "Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis." Heliyon 10.3 (2024).

Hodgkinson, Alan, et al. "High-resolution genomic analysis of human mitochondrial RNA sequence variation." Science 344.6182 (2014): 413-415.

Page 28

2.2 Childhood trajectories of white matter connectivity and mental health: insights across geographical contexts. Co-Supervisor King’s: Professor Chiara Nosarti Faculty: Institute of Psychiatry, Psychology & Neuroscience E-mail: chiara.nosarti@kcl.ac.uk Website: https://www.kcl.ac.uk/people/chiara-nosarti

Co-Supervisor ASTAR: Dr Chan Shi Yu Research Institute: Translational Neuroscience, ASTAR Institute for Human Development and Potential (ASTAR IHDP) Email: chanshiyu@a-star.edu.sg Website: https://research.a-star.edu.sg/researcher/shi-yu-chan/

Co-Supervisor ASTAR: Dr Dennis Wang Research Institute: Bioinformatics, ASTAR Institute for Human Development and Potential (ASTAR IHDP) and Bioinformatics Institute (ASTAR BII) Email: denniswang@a-star.edu.sg Website: https://research.a-star.edu.sg/researcher/dennis-wang/

Project Description

In the final trimester of pregnancy and early after birth, a baby’s brain undergoes rapid development of its “white matter”, the wiring that lets different brain regions communicate efficiently. This wiring involves the growth of nerve -fibres and their org anisation into networks. These processes continue into childhood and underpin development of important functions like language, attention and emotional control.

We can track how this wiring develops using specialised brain imaging scans (diffusion-weighted MRI), which measure how water moves along brain fibres. These scans show that different white -matter tracts mature on different timetables, and that variations in these growth paths, whether from genes, biology or environment, could be linked to later mental health outcomes.

This study will chart how white -matter connectivity evolves from infancy through to late childhood, comparing children born very preterm with those born at term. It will also assess how these brain -wiring patterns relate to cognitive, language and emotional health. With large UK and Singapore studies supplying

Page 29

brain scans, developmental and mental health data, the aim is to better understand how early brain wiring might set the stage for either resilience or vulnerability to mental health problems and help identify children who would benefit from early support.

• Year 1 (UK): Training in image processing and neuroanatomy to support theoretical and conceptual proficiency in probabilistic tractography and network-based analysis. • Year 2 (UK): Data cleaning and preparation of the ePRIME and dHCP datasets. Developing different biomarkers of neurodevelopmental outcomes based on features of white matter microstructure and connectivity development, which will be validated through regression models predicting behavioural outcomes both cross-sectionally and longitudinally. • Year 3 (UK & Singapore): Data cleaning and preparation of the GUSTO dataset. Models and features developed in Year 2 will be tailored and applied to the GUSTO dataset, to enrich analyses conducted previously. • Year 4 ( Singapore): Write-up time, and preparation of fellowships to transition into post -doctoral phase.

Representative publication from supervisors: Hadaya L, Dimitrakopoulou K, Vanes LD, Kanel D, Fenn-Moltu S, Gale-Grant O, Counsell SJ, Edwards AD, Saqi M, Batalle D, Nosarti C. Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks. Transl Psychiatry. 3;13:108 (2023). doi: 10.1038/s41398-023-02401-w.

Chan SY, Ngoh ZM, Ong ZY et al. The influence of early -life adversity on the coupling of structural and functional brain connectivity across childhood. Nat. Mental Health 2;52–62 (2024). doi: 10.1038/s44220-023- 00162-5.

Huang, J., Che, J., Kee, M.Z.L., …,Wang, D., Huang, J.Y. Linking obesity-associated genotype to child language development: the role of early -life neurology -related proteomics and brain myelination. eBioMedicine 113:105579 (2025). doi: 10.1016/j.ebiom.2025.105579.

Page 30

2.2 Excitation-Inhibition balance and imbalance in typical and atypical development. Co-Supervisor King’s: Dr Nicolaas Puts Faculty: Institute of Psychiatry, Psychology & Neuroscience E-mail: nicolaas.puts@kcl.ac.uk Website: https://www.kcl.ac.uk/people/nick-puts

Co-Supervisor ASTAR: Dr Huang Pei Research Institute: Institute for Human Development and Potential Email: huangpei@a-star.edu.sg Website: https://www.a-star.edu.sg/ihdp/our-science/research-programmes/translational-neuroscience- researchers

Project Description

E-I balance is the dynamic equilibrium between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission, critical for normal brain development and function including sensory processing, with both E -I and sensory processing believed to be dis rupted in autism. This PhD focuses on better understanding excitation-inhibition (E-I) balance in neurotypical and neurodivergent development. We will use a multimodal, longitudinal approach leveraging two distinct neuroimaging markers from two large cohorts: the neurotypical GUSTO cohort in Singapore and the autism-focused AIMS-2-TRIALS consortium.

Using fMRI -Derived functional proxies of E -I balance we will first map developmental trajectories. Using Magnetic Resonance Spectroscopy, we will gain insights into the role of neurotransmitter availability. By integrating these data, the project aims to i dentify and quantify the points at which the E -I trajectory in autism deviates from the neurotypical norm, and how this functional imbalance relates to underlying neurochemistry, subsequently affecting functional differences in sensory overload. We will also explore how genetic variability contributes to heterogeneity in development. The PhD student will gain specialized training in Big Data Analytics (fMRI, MRS, genetics, behaviour), Normative Modelling, and Multimodal Data Integration.

• Year 1: Foundation and Normative Trajectory: Neuroimaging analytics; establish the typical E -I trajectory.

Page 31

• Year 2: Atypical Profiles and Chemistry: Quantify E-I deviations; link longitudinal fMRI markers to cross-sectional MRS neurochemistry. • Year 3: Prediction and Outcomes: Assess if E -I deviations predict sensory difficulties and other outcomes • Year 4: Genetic Context and Thesis: Investigate the role of genetic variation; finalise analysis and submit the doctoral thesis.

Representative publication from supervisors: He, J. L., Oeltzschner , G., Mikkelsen, M., Deronda, A., Harris, A. D., Crocetti, D., Wodka, E. L., Mostofsky, S. H., Edden, R. A. E., & Puts, N. A. J. (2021). Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders. Translational Psychiatry , 11(1). https://doi.org/10.1038/S41398-021-01525-1.

Huang, P., Chan, S. Y., Ngoh, Z. M., Ong, Z. Y., Low, X. Z., Law, E. C., … Tan, A. P. (2024). Screen time, brain network development and socio-emotional competence in childhood: moderation of associations by parent– child reading. Psychological Medicine, 54(9), 1992–2003. doi:10.1017/S0033291724000084.

Law EC, Han MX, Lai Z, Lim S, Ong ZY, Ng V, Gabard-Durnam LJ, Wilkinson CL, Levin AR, Rifkin-Graboi A, Daniel LM, Gluckman PD, Chong YS, Meaney MJ, Nelson CA. (2023). Associations Between Infant Screen Use, Electroencephalography Markers, and Cognitive Outcomes. JAMA Pediatrics ; 177(3):311–318. doi: 10.1001/jamapediatrics.2022.5674.

Page 32

4.2 From mastication to mind: impact of oral processing on the effects of dietary flavonoids on mood, cognition and mental health. Co-Supervisor King’s: Professor Ana Rodriguez-Mateos Faculty: Faculty of Life Sciences & Medicine E-mail: ana.rodriguez-mateos@kcl.ac.uk Website: https://www.kcl.ac.uk/people/ana-rodriguez-mateos

Co-Supervisor ASTAR: Dr Aaron Thong Research Institute: Singapore Institute of Food and Biotechnology Innovation (SIFBI) Email: aaronthong@a-star.edu.sg Website: https://www.a-star.edu.sg/sifbi

Project Description

This project will investigate how the way we chew, and process foods affects the release of flavonoids, natural compounds present in fruits and vegetables, and their impact on mood, cognition, and overall mental health. Flavonoids are linked to brain benef its, but their effectiveness depends on how much is released and absorbed during digestion, which can be influenced by oral processing. Using a combination of laboratory experiments, metabolic profiling, and carefully designed human studies, the project wi ll explore the links between chewing, flavonoid bioavailability, and mental well-being.

The student will receive multidisciplinary training in food science, oral processing analysis, nutrition, metabolomics, and cognitive and psychological assessment, providing skills applicable to both academic research and the food and health sectors.

Over-arching objectives by year: • Year 1: Review literature, develop lab and analytical methods, and gain training in oral processing and cognitive assessment techniques. Conduct in vitro studies on oral bioaccesibility. • Years 2 and 3: Conduct laboratory and pilot human studies to investigate how oral processing affects flavonoid bioaccessibility and initial cognitive/mood responses. • Years 3 and 4: Carry out full -scale human intervention studies, perform advanced metabolomic analyses, and begin preparing manuscripts. • Year 4: Integrate all findings, finalise publications, disseminate results through conferences and outreach, and complete the PhD thesis.

Page 33

This research will provide novel insights into how everyday eating behaviours influence the brain benefits of plant-based diets, while equipping the student with a unique set of interdisciplinary research skills.

Representative publication from supervisors: Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double -blind randomized controlled trial. Wood E, Hein S, Mesnage R, Fernandes F, Abhayaratne N, Xu Y, Zhang Z, Bell L, Williams C, Rodriguez-Mateos A. Am J Clin Nutr. 2023 Jun;117(6):1306- 1319. https://pubmed.ncbi.nlm.nih.gov/36972800/.

Thong, A., Tan, V. W. K., Chan, G., Choy, M. J. Y., & Forde, C. G. (2024). Comparison of differences in sensory, volatile odour-activity and volatile profile of commercial plant -based meats. Food Research International, 177, 113848. https://doi.org/10.1016/j.foodres.2023.113848.

Guo, Q., Ritzoulis, C., Chen, J., Xu, J., & Wang, X. (2024). Saliva bubbles: How saliva foam impacts aroma release and retronasal perception during oral processing. LWT, 202. https://doi.org/10.1016/j.lwt.2024.116306.

Page 34

5.2 Integrating neuroimaging and omics to unravel the link between early life stress and childhood depression. Co-Supervisor King’s: Professor Paola Dazzan Faculty: Institute of Psychiatry, Psychology & Neuroscience E-mail: paola.dazzan@kcl.ac.uk Website: https://www.kcl.ac.uk/people/paola-dazzan

Co-Supervisor ASTAR: Asst. Professor Tan Ai Peng Research Institute: Institute for Human Development and Potential (IHDP) Email: tanaipeng@sics.a-star.edu.sg Website: https://www.a-star.edu.sg/sics/ourpeople/our-leaders

Co-Supervisor ASTAR: Professor Tardif Twila Zoe Research Institute: Institute for Human Development and Potential (IHDP) Email: ttardif@nus.edu.sg

Project Description

Psychiatric disorders are described as the ‘chronic disease of the young’, with a peak onset at age 14 –15 years. It is therefore critical to elucidate what factors, in the biology of the body, lead to the development of these disorders.

Early life stress (ELS) in particular is associated with the onset of depression in childhood and adolescence. However, we do not know whether this stress is also associated with changes in how the brain develops in young people. Furthermore, we do not know whether other changes, like those that happen when the body responds to stress (for example with low level inflammation) or someone’s genetic makeup also affect how the brain develops, and the risk of developing depression. To fill these gaps, this proje ct will integrate measures of brain development (that give information on volumes, function and chemical composition like diffusion imaging, resting-state fMRI, and MR spectroscopy), activation of the immune response (i.e serum CRP, cytokines, hair and salivary cortisol, urinary polyphenols), epigenetic (DNAm) and genetic (PRS scores) profiles from multiple existing datasets to develop a predictive model of depression.

Page 35

The selected PhD student will be offered the opportunity to work with highly interdisciplinary and collaborative teams across KCL and ASTAR IHDP and acquire critical skills in the following areas: advanced multimodal neuroimaging techniques, integrative omics, clinical developmental psychiatry, state-of-the-art statistical methods, and machine learning approaches. These will be complemented by a set of personal development skills in scientific writing, conference presentation and project management.

• Year 1: Complete literature review on early adversity, brain development, and depression. Register protocol and start writing up (Introduction and Methods). • Year 2: Finish review (Results and Discussion) and submit for publication; Training in Freesurfer completed; Measures of datasets to be used harmonised. The student will work on defining the neurobiological link between forms of ELS and domains of basic human neurobehavioral functioning related to childhood and adolescent depression. • Year 3: Training in creation of brain growth trajectories and integration with other data (i.e genetic profile, epigenetic modification, systemic inflammation ); completion of Aim 1 data analysis and submission of first original paper for publication. In the second part of the year, d evelopment of a predictive model for childhood and adolescent depression based on neuroimaging-omics data, to be continued in the first part of year 4. • Year 4: Completion of predictive models and of Aim 2; Submission of second original paper for publication; Writing up and submission of Thesis.

One representative publication from supervisors: Pollard R, Chen PJ, Mackes N, Lawrence AJ, Ma X, Matter M, Kretzer S, Morgan C, Harding S, Schumann G, Pariante C, Mehta M, Montana G, Nosarti C, Desrivieres S, Rodriguez-Mateos A, Dazzan P. The eBRAIN study: The impact of early adversity on trajectories of brain maturation and mental health in young adolescents - A prospective cohort study. Brain Behav Immun Health. 2022 Oct 28;26:100539. doi: 10.1016/j.bbih.2022.100539. PMID: 36388138; PMCID: PMC9640307.

Shi Yu Chan, Zhen Ming Ngoh, Zi Yan Ong, Ai Ling Teh, Michelle ZL Kee, Juan H Zhou, Marielle V Fortier, Fabian Yap, Julia L MacIsaac, Michael S Kobor, Patricia P Silveira, Michael J Meaney, Ai Peng Tan. The influence of early-life adversity on the coupling of structural and functional brain connectivity across childhood. Nat. Mental Health 2, 52–62 (2024). https://doi.org/10.1038/s44220-023-00162-5; PMID.

Page 36

6.2 RNA sensing devices to study dynamics of non -coding RNAs in neurodegeneration. Co-Supervisor King’s: Professor Joseph Bateman Faculty: Institute of Psychiatry, Psychology & Neuroscience E-mail: josephmatthew.bateman@kcl.ac.uk Website: https://www.kcl.ac.uk/people/joseph-bateman

Co-Supervisor ASTAR: Dr Sherry Shiying Aw Research Institute: Institute of Molecular and Cell Biology Email: sherryaw@a-star.edu.sg Website: https://www.a-star.edu.sg/imcb/people/sherry-aw

Project Description

Non-coding RNAs play important roles in normal and diseased states, including neurodegeneration. Study of their dynamical levels in time and space are critical for understanding their mechanisms and function; however, methods to do this are limited. Recently, methods for RNA-sensing in live cells have been developed that can enable analysis of non-coding RNA expression in real-time. Here, we propose to adapt and develop these methods for characterisation of non -coding RNAs involved in the pathology of a model of neuronal mitochondrial dysfunction. The student will select non -coding RNAs of interest, design and clone RNA sensors, test their stability and expression in cells, manipulate the levels of the RNAs of interest to determine the efficacy of the sensor s, and use the sensors in disease model systems to determine the dynamic expression of the RNAs of interest under various disease states and manipulations.

• Year 1 (KCL): Cloning and generation of UNBAR, CellReadr and CircDucker transgenic constructs at KCL. Initial testing of UNBAR, CellReadr and CircDucker reporters in Drosophila S2 cells in vitro at KCL. Selection of Drosophila non-coding RNA target candidates. • Year 2 (KCL): Generation of transgenic Drosophila expressing UNBAR, CellReadr and CircDucker constructs at KCL. Imaging of UNBAR, CellReadr and CircDucker reporters in the Drosophila brain in control flies and the Drosophila ND-75 KD mitochondrial disease model using confocal and super resolution microscopy at KCL. Request for mammalian transgene constructs and cloning in preparation for testing at ASTAR.

Page 37

• Year 3 (ASTAR): Complete design and cloning of mammalian constructs for UNBAR, CellReadr and CircDucker, and validation with positive control constructs at ASTAR. Develop sensors for top ncRNA candidates based on conservation, function and localisation. • Year 4 (First 6 months at ASTAR and last 6 months at KCL): Validation of constructs in neurons differentiated from human SH-SY5Y or mouse Neuro2a cells to determine if pathways/mechanisms are conserved, and assay of ncRNAs of interest in related disease model cells at ASTAR. Preparation of manuscripts, thesis planning, writing and thesis submission at KCL.

Representative publication from supervisors: Mandy Yu-Theng Lim1#, Chermaine Tan1#, Charannya Sozheesvari Subhramanyam1#, Shi Jie Teo1, Louis de Falco Jr, Samuel Kevin Pasaribu, Chong Hui Koh, Dheeraj Rayamajhi, Jieying Chi, Shengnan Li, Dave Wee, Sudipto Roy, Roland Huber and Sherry Shiying Aw. A p rogrammable ribozyme for RNA signal transduction (Accepted pending text revisions, Nature Communications).

Esra Senol, Menghan Wang, Yongjuan Xin, Zhuolei Jiao, Hasan Mohammad, Xin Yi Yeo, Tengxiao Si, David M Young, Hua Huang, Yingxue Wang, Qin Li, Sang Yong Jung, Xiaohong Xu, Pei Zhang, Yu Fu (2025). Brain-wide input-output analysis of tuberal nucleus somatostatin neurons reveals hierarchical circuits for orchestrating feeding behavior. Nature Communications 16:5627.

L. Granat, D.Y. Knorr, D.C. Ranson, E.L. Hamer, R.P. Chakrabarty, F. Mattedi, L. Fort -Aznar, F. Hirth, S.T. Sweeney, A. Vagnoni, N.S. Chandel, J.M. Bateman (2023). Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mi tochondrial complex I deficiency. PLOS Genetics ,19(7): e1010793.

Research areas