# Discovery of Aging-Associated Mechanisms Causing Expansion and Progression of Clonal Hematopoiesis of Indeterminant Potential (CHIP)

> **NIH NIH R01** · JACKSON LABORATORY · 2024 · $489,247

## Abstract

PROJECT SUMMARY/ABSTRACT
Clonal hematopoiesis of indeterminant potential (CHIP) is an aging-associated condition that confers increased
risk of progression to hematologic disorder and a decreased overall survival rate. The incidence of CHIP
increases substantially with advancing age, present in 10-15% of individuals aged 70 years or older. CHIP is a
significant health concern as the proportion of individuals ≥ 65 years old in the United States is expected to
increase from 15% of the population in 2014 to 24% by the year 2060. CHIP is caused by somatic mutations
that confer a selective advantage to hematopoietic stem cells (HSCs) and their progeny, which can be easily
detected using next-generation sequencing. However, there are currently no methods to identify individuals in
which CHIP will progress to hematologic disorder, and no therapies to prevent this progression. The long-term
goal of this research is to develop novel strategies to extend healthy hematopoietic function during aging and
prevent aging-associated hematologic disorders. The overall objective of this proposal is to determine the
aging-associated cellular and molecular alterations that promote the expansion of CHIP-mutant clones and
their progression to hematologic disorder. The rationale is that the underlying mechanisms will be prime,
modifiable targets for detection and mitigation of high-risk CHIP. Preliminary data describe a technically
innovative mouse model in which the timing of CHIP development and progression can be strictly controlled.
This is the only model to date that recapitulates in vivo CHIP progression as it occurs in humans. Using this
model, the aged bone marrow (BM) microenvironment was shown to accelerate CHIP expansion and
progression, and correlated with an age-related increase in the concentration of pro-inflammatory cytokines in
the BM microenvironment. These data support the central hypothesis that alterations in the aged BM
microenvironment increase the selective advantage of CHIP-mutant HSCs and their progeny causing CHIP
expansion and progression. This project will use cellular and molecular biological approaches in aged mice to
achieve the following specific aims: AIM 1. Discover pathogenic somatic mutation(s) selected for by an aged
BM microenvironment during CHIP expansion and progression; AIM 2. Delineate the mechanisms by which the
aged BM microenvironment accelerates CHIP expansion and progression; and AIM 3. Determine the extent to
which chronic inflammation causes CHIP expansion and progression. The proposed research is conceptually
innovative because it is the first to define the important role of the aged BM microenvironment in causing CHIP
expansion and progression. This study is significant because it will define the cellular and molecular
mechanisms that underlie progression of CHIP to hematologic disorder and provide a fundamental basis for
the development of biomarkers to predict high-risk CHIP and novel prophylactic therapies to mitig...

## Key facts

- **NIH application ID:** 10865013
- **Project number:** 5R01AG069010-05
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Jennifer Jean Trowbridge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $489,247
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865013

## Citation

> US National Institutes of Health, RePORTER application 10865013, Discovery of Aging-Associated Mechanisms Causing Expansion and Progression of Clonal Hematopoiesis of Indeterminant Potential (CHIP) (5R01AG069010-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10865013. Licensed CC0.

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