# Multi-omic dissection of clonal hematopoiesis-associated diseases

> **NIH NIH R00** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $249,000

## Abstract

Project Summary
Self-renewing cell populations accumulate somatic mutations with aging and/or in response to environmental
insult and chronic inflammation. Most of these mutations in normal tissues have no functional consequence. In
rare cases, these somatic mutations can confer a selective advantage leading to clonal expansion in
hematopoietic stem cells, a phenomenon termed 'Clonal Hematopoiesis of Indeterminate Potential' (CHIP).
CHIP has been associated with a selective range of non-hematopoietic conditions, including coronary artery
disease, stroke, heart failure, venous thromboembolism, chronic obstructive pulmonary disease, chronic liver
diseases, and osteoporosis. However, the molecular mechanisms by which CHIP specifically promotes these
diseases remain largely unknown. The overarching goal of this proposal is to molecularly connect CHIP with
the development of associated diseases through developing and applying statistical and machine learning
methods to multi-omics data in the NHLBI Trans-Omics for Precision Medicine (TOPMed), UK Biobank, and
Mass General Brigham Biobank (MGBB). Specifically, I propose the following aims. In Aim 1, I will develop a
statistical method that combines multiple proteins implicated in the same pathway to improve discovery and
facilitate translational insights for proteomics-based association analyses. The combined protein quantitative
traits generated by this method will be used in the following aims. In Aim 2, I will examine how the presence of
CHIP and each CHIP driver gene specifically promote certain diseases through (1) identifying the proteomic
signatures of CHIP and quantifying the mediation effects to associated diseases and (2) evaluating the
potential modifications of CHIP-associated diseases by the expression levels of genes implicated in diverse
molecular factors. In Aim 3, I will evaluate how the progression of CHIP promotes associated diseases. I will
examine associations between longitudinal change in the number and size of CHIP clones and incident
disease risks, as well as generate bulk and single-cell RNA sequencing data among CHIP carriers with or
without osteoporosis, a disease strongly associated with CHIP but understudied, and test for differential gene
expressions between the two groups. This project's successful execution will identify the mechanisms
underlying CHIP-associated disease risks to prioritize therapeutic targets and advance precision medicine
goals.

## Key facts

- **NIH application ID:** 11165567
- **Project number:** 4R00HG012956-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zhi Yu
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2024-09-17 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11165567

## Citation

> US National Institutes of Health, RePORTER application 11165567, Multi-omic dissection of clonal hematopoiesis-associated diseases (4R00HG012956-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11165567. Licensed CC0.

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