# The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia

> **NIH NIH R01** · CORIELL INSTITUTE FOR MEDICAL RESEARCH · 2024 · $488,809

## Abstract

The role of GSK3/PPAR-δ/FAO/mitophagy pathway in regulating
 hematopoietic stem cell homeostasis and function
Abstract
Hematopoietic stem cells (HSCs) possess the abilities to both produce stem cells, a
property known as self-renewal, and give rise to all differentiated hematopoietic lineages.
Clinically, HSCs are therapeutically valuable for transplantation in treatment of various
hematologic malignances. Despite remarkable progress made in the research of HSCs
during the past three decades, the molecular mechanisms regulating HSC homeostasis
and function are still not fully understood.
Our previous published showed that GSK3 plays an essential role in regulating HSC
homeostasis. Specifically, knockdown of Gsk3 promote transient expansion and long-term
exhaustion of HSC in vivo. Our new preliminary studies demonstrated that GSK3 functions
through PPAR-δ/FAO/mitophagy pathway to regulate HSC division symmetry; inhibition
of GSK3 induces mitophagy and conversely, blocking PPAR-δ/FAO/mitophagy can
reverse the enhanced self-renewal phenotype that is associated with GSK3 inhibition. In
this study, we will first examine how GSK3 regulates PPAR-δ, which in turn regulates
mitophagy and HSC division symmetry. Secondly, we will investigate whether loss-of-
function of Ppar-δ, Park2 or Pink1 (two mitophagy key regulators) reverse the functional
defect of Gsk3b-deficient HSC in vivo. Lastly, we will explore whether GSK3 controls FAO
and lipid metabolism to regulate HSC function and homeostasis.
Our study will provide significant new insights into the molecular mechanisms underlying
GSK3-dependent regulation of HSC homeostasis and function. The knowledge learned
may facilitate bone marrow transplantation for treating diverse hematological diseases.

## Key facts

- **NIH application ID:** 10757733
- **Project number:** 5R01HL157118-03
- **Recipient organization:** CORIELL INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Jian Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $488,809
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757733

## Citation

> US National Institutes of Health, RePORTER application 10757733, The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia (5R01HL157118-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10757733. Licensed CC0.

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