# APOL1 associated disease spectrum

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $570,623

## Abstract

Each year, at least 1.7 million adults in the US develop sepsis and nearly 270,000 Americans die of
sepsis. 1 in 3 patients who dies in a hospital has sepsis. African Americans have a 67% higher severe
sepsis hospitalization rate and 20% more likely to die of sepsis compared to whites even after adjusting for
co-variates. Close to 45% African American carry at least one APOL1 risk allele. Variants in APOL1 are thought
to have arisen as a result of positive genetic selection, as they confer resistance against Trypanosome brucei
rhodesiense, a parasite that causes African sleeping sickness. While having one risk variant imparts this crucial
resistance against sleeping sickness, having two risk alleles significantly increases the risk of developing kidney
disease.
Recent genetic and mouse model studies indicate that APOL1 risk variant (RV) in endothelial cells might
explain the increased sepsis susceptibility and severity in African Americans.
Aim1. Define the role of RV APOL1 in sepsis in mouse models and patients. A. Characterize sepsis severity
in mice with conditional inducible expression of RV and reference APOL1 in endothelial cells, kidney and liver
cells. B. Examine the association between APOL1 RV genotype and sepsis incidence and severity in the
Upenn (PMBB) and Vanderbilt (BioVU) Biobanks. C. Determine the association of plasma APOL1 level and
sepsis severity in the MESSI cohort.
Aim2. Define endothelial RV APOL1 induced pathology. A. Characterize RVAPOL1 endotheliopathy such
as inflammation, permeability and coagulation changes using isogenic gene edited RV APOL1 human and
mouse transgenic endothelial cells. B. Using single cell gene expression characterize changes associated with
RV APOL1-induced endotheliopathy in vivo. C. Describe the cellular trafficking defect induced by RV APOL1
such as endocytosis, autophagy, and mitophagy in EC.
Aim3. Determine whether pharmacological, or cell type specific genetic targeting of the inflammasome
(NLRP3) and nucleotide sensing pathways (STING) alleviate endothelial RV APOL1 associated
endotheliopathy and sepsis
RV APOL1 is a critical determinant of health disparities affecting millions of people in the US. Our study will
define the role endothelial of RV APOL1 in sepsis and could identify novel drugs to target RV APOL1

## Key facts

- **NIH application ID:** 10298299
- **Project number:** 2R01DK105821-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KATALIN SUSZTAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,623
- **Award type:** 2
- **Project period:** 2015-12-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298299

## Citation

> US National Institutes of Health, RePORTER application 10298299, APOL1 associated disease spectrum (2R01DK105821-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10298299. Licensed CC0.

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