# Genetic Variants of Immune Dysregulation and Thrombotic Microangiopathy in Severe Pediatric Sepsis Induced Organ Dysfunction

> **NIH NIH K23** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $163,028

## Abstract

Sepsis results in 75,000 pediatric and one million adult hospital admissions per year,
costing $20 billion dollars and 200,000 lives in the US annually. Risk for severe infection has a
heritable component, and offspring of parents who suffer early death from infection have a 6-fold
increased risk of infectious death even when adopted into other households. However, the
specific sites of genetic variation that convey this are poorly understood. Here, I propose to use
whole exome sequencing to identify septic individuals with shared genetic risk for heritable
thrombotic microangiopathy and immune dysregulation, and determine if these genotypes
associate with clinical, cytokine and organ injury patterns typical of these thrombotic
microangiopathy and hyperinflammatory disorders during severe sepsis, phenotypes that have
been associated with poor outcome. My overall objective in this career development award
is to identify genotypes that confer risk for development of thrombotic microangiopathy
and immune dysregulation in severe sepsis, and validate these findings in multiple sepsis
cohorts. My central hypothesis is that immunologically active variants that cause primary
immunologic disorders characterized by thrombotic microangiopathy and hyperinflammation will
be linked to the development of related phenotypes and organ failure patterns in severe sepsis. I
will test my central hypothesis in three specific aims: 1) Confirm the link between thrombotic
microangiopathy-related variants and complement hyperactivation in severe sepsis by direct
measurement of complement activation products and archetypal organ injury biomarkers, 2)
Explore the relationships between immune dysregulation genotype and clinical, immunologic and
organ injury patterns typical for cytotoxic defects and dysfunctional macrophage and T-cell
interaction and 3) externally validate our previous IEI genotype-phenotype associations in novel
cohorts. This approach may allow for identification of specific genetic risk variants, as well as
outcome-associated disease mechanisms as targets for further study in severe sepsis. Closely
mentored by experts in pediatric sepsis, immune dysregulation, genomic medicine, bioinformatics
and data science, this award will provide essential training in coding, genetic epidemiology,
statistical assessment of genomic data, and prospective clinical trials. As the foundation for a
career, this project will hone my skills in genomic research design and analysis necessary to study
precision approaches to pediatric critical care.

## Key facts

- **NIH application ID:** 10828821
- **Project number:** 5K23GM148827-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kathryn MARY Kernan
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $163,028
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828821

## Citation

> US National Institutes of Health, RePORTER application 10828821, Genetic Variants of Immune Dysregulation and Thrombotic Microangiopathy in Severe Pediatric Sepsis Induced Organ Dysfunction (5K23GM148827-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10828821. Licensed CC0.

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