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PhD Opportunity: Why Does Metabolic Disease Damage Some Organs and Spare Others?
I am looking for a PhD student through VCU's Integrative Life Sciences (ILS) PhD program to develop a dissertation at the intersection of human genetics, biostatistics, and liver disease. You would work with me and my collaborators, Dr. Ekaterina Smirnova and Dr. Steve Hoang.
Fatty liver disease and related metabolic conditions can lead to liver failure, heart disease, or kidney disease, but we cannot yet predict which organ a given patient will lose first. Some genetic variants make this puzzle sharper: they protect the heart while harming the liver. Our group is building a framework to study this using the NIH All of Us Research Program, a large and ancestrally diverse cohort with genomes linked to health records.
Open questions a dissertation could address include:
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Do genetic variants cluster into shared biological "axes" that explain organ-specific risk?
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Can genetics tell us which organ is most at risk for an individual, beyond standard clinical measures?
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Does organ-specific genetic risk differ across ancestries, and what does that mean for equitable risk prediction?
You will help shape the direction of your thesis within this area. Along the way you will gain hands-on training in human genetics, survival and competing-risks statistics, and large-scale biobank data, and you will work toward first-author publications.
Good fit if you are: curious about human disease and genetics, comfortable with (or eager to learn) coding in R or Python, and interested in work that connects computation to clinical questions. Backgrounds in biology, bioinformatics, statistics, or related fields are all welcome.
Funding: This position is supported by a graduate teaching assistantship, and TA duties in undergraduate bioinformatics courses are part of the appointment.
How to apply:
Apply to the Integrative Life Sciences PhD program and mention this project in your statement. Please also email me at [gbbulut@vcu.edu] with your CV and a few sentences about your interests.
Bulut lab Goals:
Define the cellular mechanisms perturbed by metabolic disease in adipose tissue, hypothalamus, and liver — using computational biology and multi-omics to reveal cellular states, abundance, and signaling among them.
Aim 1. What builds the macrophage compartment of obese adipose tissue?
Obesity expands adipose tissue macrophages several-fold, and single-cell work has resolved that compartment into many states, including the lipid-associated program. Most of that work asks what the macrophages become. We asked what supplies them.
Deleting Klf4 in Myh11-lineage smooth muscle cells and pericytes leaves mice equally obese but halves the macrophage compartment and improves glucose tolerance. Returning to those single-cell libraries, we found the deficit is on the supply side: perivascular matrix, chemokine, and CSF-family ligands all fall, while Ccr2 and Csf1r expression and macrophage proliferation are unchanged. Monocytes still arrive and can still hear — what they stop receiving is the instruction to mature into the Spp1⁺ state that dominates obese tissue. The same perivascular program tracks with BMI in human adipose tissue.
Open projects
1) Does acute fasting reverse the perivascular supply program, or does it persist as a chronic imprint?
2) Do the supply program and the Spp1⁺ compartment recover together during weight loss and GLP-1 receptor agonist treatment, and in what order?
3) Does the mechanism differ by sex and by depot? Our original lineage-tracing model was male only; we now have female data, and human atlases contain both sexes.
Aim 2. Why do leptin-sensing hypothalamic neurons stop responding?
Leptin reports adiposity to the brain. In obesity leptin is abundant and the brain behaves as though it is scarce. We are asking where in the circuit that failure sits.In public hypothalamic single-cell data, Agrp/Npy neurons carry the highest leptin-receptor activity of any population at every dietary state. Acute fasting raises their ER stress more than that of any other cluster and increases leptin-receptor activity, while the size of the population does not change — a shift in cell state, not cell number. Across the energy axis, leptin and the neuronal response move in opposite directions.
Open projects
1) Do the canonical brakes on leptin signalling — Socs3, Ptpn1 — account for the loss of responsiveness, and which arm of the unfolded protein response is engaged?
2) Is reduced responsiveness a problem of access or of signalling? Tanycytes gate leptin's entry into the arcuate nucleus, and their abundance falls sharply with fasting.
3) Does central incretin signalling reach adipose tissue? Deleting GLP-1 and GIP receptors in the central nervous system alters peripheral transcriptomes more than the drug itself does.3. Why does the same liver insult injure some people far more than others
Ongoing Collaborations:
Collaborative work with the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, and with the NIMBLE consortium. This is consortium-scale work rather than a trainee project.
Alcohol-associated and metabolic liver disease frequently co-occur, and the PNPLA3-I148M variant raises risk in both; in combination with obesity and heavy drinking the risk is supra-multiplicative. To understand molecular mechanisms we have integrating metabolomics and single-nucleus transcriptomics.
At human scale, combinatorial models of biomarkers in the NIMBLE cohort identify MASLD sub-phenotypes with high precision, and show that different markers dominate at different fibrosis stages. This work has potential to extend into UK Biobank and the All of Us Research Program.
How we work
The program is computational. We rely heavily on public data, because far more has been generated than has been fully analyzed, and we build the tools that make that reuse trustworthy — multipletR, an R package for adaptive detection of multi-species multiplets in patient-derived xenograft single-cell data, and a modular wrapper that runs multiple annotation methods against multiple reference atlases and reports where they disagree rather than forcing a label.
Working with me
Projects are modular, require computing rather than specialized facilities, and produce publishable results on the timescale of an academic year. Students in the lab have presented at ISMB and NCUR, secured competitive research funding, and are first authors on manuscripts in preparation. If one of the open projects above sounds interesting, let me know!
Mentored Student Research Projects
Ajay Manohar
Ajay graduated from VCU recently and is currently pursuing a Master's degree in Northeastern University. Ajay is looking into improving cell type annotation methods in single cell RNAseq.
Riya Khanna
Riya will investigate cellular crosstalk in the brain from and to leptin receptor expressing cells in response to insulin resistance and obesity
Johana Johnson
Johana is a sophomore majoring in Bioinformatics, Genomics concentration and minoring in Biology and Chemistry. She is currently on track to complete an Accelerated Master’s degree in Bioinformatics. She is interested in pursuing a career in genomic and pharmaceutical medicine. Johana worked on adipose tissue macrophages heterogeneity project.
Sanjana Varghese
Sanjana is helping draft the manuscript on macrophage heterogeneity in adipose tissue stromavascular fraction in Summer 2026.
Lavanya Sharma
Lavanya and Sanjana are drafting the manuscript for adipose tissue macrophages.
Patrick Delaney
Patrick is learning the method of bulk RNAseq and will analyze liver sequence data with increasing fibrosis stages.
Haneke Aguilar
Haneke is interested in studying the impact of obesity drugs on GLP1R using mouse bulk RNAseq datasets.
Anisha Agarwal
Anisha will help identify Spp1+ macrophages in human adipose tissue scRNAseq datasets.
Research Mentoring at William & Mary
Beryl Jiang
Beryl is a Biology and Computer Science double major at WM. She will work to investigate macrophage heterogeneity within the adipose tissue stromovascular fraction. She will compare the macrophage types in lean vs obese condition to understand changes in response to obesity.
Yuqi Pang
Yuqi is a fourth year student majoring in B.S. Statistics at UVA. She will work with Beryl on the macrophage heterogeneity project in adipose tissue using scRNA seq datasets.
Caelen Grange
Caelen is a senior from Northern Virginia, majoring in Biology and minoring in Finance. He works as a personal trainer and as Co-President of the W&M Cycling Club. He likes to cook, swim, read, and watch movies. Caelen will work on the lymphatic smooth muscle cell project.
Anna Sepulveda
Anna is a Kinesiology and Neuroscience major junior at WM. She joined our research group to investigate vascular cell heterogeneity in the adipose tissue and changes upon obesity diet. Anna and Caelen are working on understanding lymphatic vasculature and how it changes with obesity.
Previously mentored students
Isabella Napoli, undergrad at VCU
Jason LaPierre, Melanie Jimenez, Morgan Montana (undergrad at WM)
Tehya Niide, Kritihika Layagala (undergrad at WM)
Lillian Waller, Medical Resident at VCU
Ana Tsiskarishvili, District Manager at Vector Marketing
Sophia Kirmani, UVA graduate.