Sankar Ghosh
Columbia University, NY·Microbiology & Immunology
Much of the genetic risk for common diseases sits in parts of the genome that do not code for proteins, and figuring out what those stretches of DNA actually do is one of the central problems in disease genetics. Two projects here take that problem in different directions: one dissects a non-coding RNA linked to inflammatory bowel disease and its control of immune cells in the gut, the other examines a protein that assembles part of the mitochondrial machinery and may connect failing mitochondria to Alzheimer's disease.
- Fields
Microbiology & Immunology
Neuroscience
Genetics
- Topics
inflammatory bowel disease
colitis
long non-coding RNA
- Grants
- 2 known grants, through Jan 2030
What they work on
- Determine the molecular mechanism by which the long non-coding RNA lnc15 post-transcriptionally sets the level of Tbet messenger RNA, a master regulator of T cell identity.
- Define how altered Tbet levels downstream of lnc15 change the function of conventional CD4+ helper T cells and regulatory T cells that suppress inflammation.
- Test how IBD-associated single nucleotide polymorphisms alter the expression and folded secondary structure of lnc15, and the functional consequences of those changes.
- Establish lnc15's role in experimental colitis using knockout mice in dextran sulfate sodium-induced and T cell transfer colitis models, and relate it to IBD susceptibility in patients.
- Characterize how ECSIT, an assembly factor for mitochondrial complex I, governs mitochondrial function, reactive oxygen species production and mitochondrial quality control in neurodegeneration.
- Test the mitochondrial cascade hypothesis directly in murine models of Alzheimer's disease and probe how dysregulation of ECSIT expression or function relates to disease development.
More about the research
The first project addresses inflammatory bowel disease (IBD), a chronic autoimmune condition marked by severe intestinal inflammation, a leakier gut lining and heightened immune responses, whose cause remains unclear. Genome-wide association studies, which scan many genomes for variants tied to disease, have found that most IBD-associated single nucleotide polymorphisms (single-letter DNA differences) fall outside protein-coding genes, with many landing in long non-coding RNAs, RNA molecules that regulate other genes rather than making protein. The team has characterized one such molecule, which they named lnc15. Their preliminary work shows lnc15 is reduced in IBD patients, that the IBD-associated version of the gene both lowers its expression and changes its folded shape, and that mice lacking lnc15 are more susceptible to colitis in two models: chemically induced colitis using dextran sulfate sodium, and colitis triggered by transferring T cells. Mechanistically, lnc15 appears to act after transcription to set levels of Tbet messenger RNA, a master regulator of T cell identity, thereby shaping both conventional CD4+ helper T cells and regulatory T cells that restrain inflammation. The project will work out how lnc15 controls Tbet, how altered Tbet changes these two T cell populations, and how the disease-associated variants alter lnc15's structure and function.
Why it matters
Inflammatory bowel disease is currently incurable, and most of its known genetic risk sits in non-coding DNA that cannot yet be translated into treatments; showing how the lnc15 RNA tunes gut T cell responses could explain why certain variants raise risk and suggest where to intervene. For Alzheimer's disease, where existing drugs only ease symptoms, establishing whether ECSIT-driven mitochondrial dysfunction triggers neurodegeneration could point toward therapies aimed at disease progression rather than symptoms.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Laurie Harrington
University of Alabama at Birmingham, AL·Microbiology & Immunology
Determine how the transcription factor STAT4 directs the accumulation of Th17 cells, a pro-inflammatory CD4 T cell subset, in inflamed peripheral tissues.
Pawel Kiela
University of Arizona, AZ·Microbiology & Immunology
Determine whether loss of NAD+ or excess PARylation by the enzyme PARP1 is the main driver of experimental colitis, using PARP1 knockout mice and drug inhibition.
Theresa Torres Pizarro
Case Western Reserve University, OH·Microbiology & Immunology
Identify the cell types in subepithelial ST2+ patches, cells that respond to the signaling molecule IL-33 and sit over colon polyps, in AOM/DSS-treated and Winnie mice, and test their function in tissue outside the body.
The school
Columbia University: 89 labs on PI Pages, $1.4B a year on research, 625 research doctorates a year.
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