# Hematopoietic stem cell mutations and ischemic cardio-metabolic disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $485,033

## Abstract

SUMMARY
The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the
causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate, and
remains unexplored in the setting of cardiovascular disease (CVD), the leading cause of death in elderly
individuals. Recent large exome sequencing studies in humans have shown that aging is inevitably associated
with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive
growth advantage to the mutant cell and thus allow its clonal expansion (clonal hematopoiesis). Unexpectedly,
these somatic mutations were associated with a higher rate of cardiovascular-related deaths,
suggesting a previously unrecognized link between somatic mutations in bone marrow-derived cells
and CVD. Recently, we reported that pre-cancerous driver mutations in Tet2 that occur in hematopoietic stem
cells may be causally linked to cardiovascular disease. However, whether there is a causal connection
between other clonal hematopoiesis genes and CVD remains unclear and the potential underlying
mechanisms are completely unknown; and this is the scientific premise of the proposed research. Here, we will
use a lentivirus/CRISPR gene editing approach to manipulate other hematopoietic stem cell driver genes and
assess their impacts in a multi-faceted model of cardio-metabolic disease.

## Key facts

- **NIH application ID:** 10161815
- **Project number:** 5R01HL141256-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** KENNETH WALSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $485,033
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10161815

## Citation

> US National Institutes of Health, RePORTER application 10161815, Hematopoietic stem cell mutations and ischemic cardio-metabolic disease (5R01HL141256-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10161815. Licensed CC0.

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