# Impact of hematopoietic stem progenitor cell dysfunction on tissue recovery from ischemic injury in metabolic syndrome

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2020 · $405,000

## Abstract

Increasing evidence links obesity-related health problems, such as insulin resistance,
cardiovascular disease and impaired tissue repair, with chronic inflammation. Although
dysregulated hematopoietic stem progenitor cell (HSPC) responses are known to be
involved, the mechanism(s) underlying obesity-induced dysregulation of inflammation
and its downstream impact on healing following ischemia remain unclear. The long-term
goal of this study is to understand mechanisms though which obesity and insulin
resistance impairs healing after ischemic injury, with a specific focus on epigenetic
regulation of HSPCs and dysregulation of inflammation. We hypothesize that obesity and
insulin resistance induces HSPC dysregulation that leads to increased supply of
inflammatory monocytes, which in turn contributes to prolonged inflammation and
impaired healing after ischemic tissue injury. Our preliminary data suggest that this
pathway involves mitochondria (mit)-reactive oxygen species (ROS)-induced epigenetic
dysregulation in high fat diet (HFD)-induced prediabetic mice. In this study, we propose:
(1) To determine the role of prediabetes-induced ROS in histone-3 lysine-4 (H3K4)
methylation in HSPCs. We hypothesize that HFD-induced mit-ROS increases H3K4me3
in HSPCs by inducing SET7/9 methyltransferase and inhibiting JARID demethylase
activation. (2) To determine the role of prediabetes-induced ROS in HSPC monopoiesis
following hindlimb ischemia. We hypothesize that HFD increases inflammatory
monopoiesis of HSPCs via mit-ROS-induced H3K4me3. (3) To determine the cell
autonomous role of prediabetes-dysregulated HSPCs in tissue recovery following
hindlimb ischemia. We hypothesize that prediabetes-dysregulated HSPCs enhance
inflammation and impair tissue recovery after hindlimb ischemia in a cell-autonomous
and mit-ROS-dependent manner. Our proposed study will begin to elucidate the
mechanisms involved in HSPC dysregulation in obesity-related conditions and its impact
on inflammatory responses and healing following ischemic injury. If successful, our data
will implicate mit-ROS and downstream H3K4 methylation as a key pathway for inducing
prediabetes-induced epigenetic memory in HSPCs, and will provide insight into novel
therapeutic targets for ischemic cardiovascular diseases in patients with prediabetic
pathology.

## Key facts

- **NIH application ID:** 10003237
- **Project number:** 5R01DK111489-04
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Norifumi Urao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003237

## Citation

> US National Institutes of Health, RePORTER application 10003237, Impact of hematopoietic stem progenitor cell dysfunction on tissue recovery from ischemic injury in metabolic syndrome (5R01DK111489-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003237. Licensed CC0.

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