# From genetic variants to mechanisms: understanding drivers of inflammation

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $437,500

## Abstract

PROJECT SUMMARY
The immune system is an amazingly complex biological system characterized by rapid and precise cell-cell
communication, danger signaling, migration, deployment of effector functions and resolution of inflammation to
avoid self-harm. Yet despite its essentiality, the human immune system also displays remarkable inter-individual
variability. Understanding what accounts for these inter-individual differences will set the stage for personalized
therapies for chronic inflammatory diseases, which constitute a major medical and public health burden. Although
it is clear many chronic inflammatory diseases have a strong genetic component, we still lack a precise
understanding of how specific gene variants specify aberrant immune responses on an individual patient-by-
patient basis. As a result, many patients receive broadly immunosuppressive treatments that do not address the
root causes of their disease, may be ineffective or toxic, or lead to treatment-refractoriness. Most research on
the genetic basis of inflammatory diseases has been performed using genome-wide association studies (GWAS)
or single-gene knockout mouse models. However, both of these approaches are subject to important caveats:
GWAS are predicated on an assumption of genetic homogeneity (e.g. disease is caused by common variants,
shared by those affected); while human and murine orthologs of the same gene often control vastly different
immunological phenotypes. To partially address this gap, my work combines unique capabilities in the analysis
of large EHR-linked biobanks and rare cases of Mendelian disease, together with wet-lab approaches to discern
the functional impact of novel variants on immune signaling pathways and cellular phenotypes. With these tools,
my lab will identify genes and immune pathways that have large effects on inflammatory disease pathogenesis,
and thus are strong candidates for therapeutic targeting. We identify genes and variants with strong impacts on
disease through the in-depth study of rare patients with monogenic (Mendelian) inflammatory diseases. I have
built a unique patient cohort along with a robust mutation discovery pipeline and used this tool to identify
novel genetic variants in patients with severe pediatric inflammatory diseases. I have also developed wet lab
capabilities to perform diverse molecular and cellular experiments to determine how each mutated protein
causes immune dysregulation including the use of cutting-edge single cell assays in patient-derived samples.
To determine how more common and non-coding variants in the same genes impact diverse inflammatory
disease processes, I will use Vanderbilt's unique biobank of DNA from discarded clinical samples linked to de-
identified electronic health records (EHR) to find new genotype-phenotype associations. Findings will be
validated in two other independent large biobanks. The use of human genetic data, and especially insights
gleaned from Mendelian genetic studies such as thi...

## Key facts

- **NIH application ID:** 10941593
- **Project number:** 1R35GM155339-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Janet G Markle
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,500
- **Award type:** 1
- **Project period:** 2024-06-05 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941593

## Citation

> US National Institutes of Health, RePORTER application 10941593, From genetic variants to mechanisms: understanding drivers of inflammation (1R35GM155339-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10941593. Licensed CC0.

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