# Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging

> **NIH NIH R01** · NORTH DAKOTA STATE UNIVERSITY · 2024 · $435,143

## Abstract

Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging
Abstract
Cerebrovascular dysfunction in aging increases risk for the development of cognitive decline and
Alzheimer’s disease. Adult hematopoietic stem/progenitor cells (HSCs) play an important role in
maintaining vascular homeostasis. Our novel preliminary studies identified that exosomes,
nanovesicles, derived from HSCs of Older subjects (Old-HSC-Exos) induced dysfunction the
human brain microvascular endothelial cells (BMECs) characterized by impaired mitochondrial
bioenergetics and attenuated angiogenesis. In agreement with these findings, brain microvessels
(BMVs) from Old mice showed imbalance in mitochondrial bioenergetics compared to the Young-
BMVs. Furthermore, we have discovered that activation of Mas-related G-protein coupled
receptor, D (MrgD) reversed age-associated impairment in bioenergetics in BMVs.
This proposal tests the hypothesis that HSC-derived exosomes from Older individuals induce
imbalance in the mitochondrial bioenergetics and impair cerebrovascular function resulting in
cognitive decline. We further hypothesize that activation of MrgD is novel pharmacological
approach for the treatment of vascular dementia. We will evaluate molecular cargo in the
exosomes derived from Young and Old individuals by RNAseq analysis and determine the
mitochondrial functions of selected molecules in the brain MVECs and BMVs. The potential of
Mrgd activator Alamandine in reversing the detrimental effects of Old-HSC-Exos in the endothelial
mitochondria and BMVs. We’ll determine the detrimental effects of Old-HSC-Exos in murine
BMVs and test their potential to induce vascular dementia and cognitive decline in the Young and
Old mice. The potential benefits of MrgD activators in Old-HSC-Exos-induced vascular dementia
will be evaluated in vivo. Lastly, pharmacology of MrgD activators will be evaluated in APP/PS1
mice. If carried out successfully, this proposal will provide proof-of-concept for a novel role of
HSC-exosomes in the pathology of vascular dementia and for MrgD as a promising target for the
treatment.

## Key facts

- **NIH application ID:** 10906972
- **Project number:** 5R01AG056881-07
- **Recipient organization:** NORTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Yagna Jarajapu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,143
- **Award type:** 5
- **Project period:** 2017-09-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906972

## Citation

> US National Institutes of Health, RePORTER application 10906972, Stem Cell-Derived Exosomes, MrgD and Vascular Cognitive Impairment in Aging (5R01AG056881-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906972. Licensed CC0.

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