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

Award Number: R01AG056881
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $435,143 )
2024	2024	NORTH DAKOTA STATE UNIVERSITY	1301 12TH AVE N	FARGO	ND	58102	CASS	USA	Aging Research	003	7	7/3/2024	NON-COMPETING CONTINUATION	$435,143
2024	2023	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Aging Research	000	6	12/16/2023	COMPETING CONTINUATION	$0
2024	2023	NORTH DAKOTA STATE UNIVERSITY	1301 12TH AVE N	FARGO	ND	58102	CASS	USA	Aging Research	002	6	5/30/2024	COMPETING CONTINUATION	$83,722
2024	2021	NORTH DAKOTA STATE UNIVERSITY	1301 12TH AVE N	FARGO	ND	58102	CASS	USA	Aging Research	001	5	5/30/2024	NON-COMPETING CONTINUATION	-$83,722
														Subtotal = $435,143

Issue Date FY: 2023 ( Subtotal = $457,643 )
2023	2023	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Aging Research	002	6	8/14/2023	COMPETING CONTINUATION	$457,643
2023	2021	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Aging Research	000	5	6/17/2023	NON-COMPETING CONTINUATION	$0
2023	2021	NORTH DAKOTA STATE UNIVERSITY	1310 BOLLEY DR	FARGO	ND	58105	CASS	USA	Aging Research	001	5	8/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $457,643

Issue Date FY: 2021 ( Subtotal = $253,750 )
2021	2021	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	000	5	6/3/2021	NON-COMPETING CONTINUATION	$253,750
														Subtotal = $253,750

Issue Date FY: 2020 ( Subtotal = $309,665 )
2020	2020	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	000	4	6/4/2020	NON-COMPETING CONTINUATION	$309,665
														Subtotal = $309,665

Issue Date FY: 2019 ( Subtotal = $334,665 )
2019	2019	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	000	3	5/21/2019	NON-COMPETING CONTINUATION	$284,665
2019	2019	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	002	3	9/13/2019	SUPPLEMENT FOR EXPANSION	$0
2019	2019	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	001	3	8/5/2019	SUPPLEMENT FOR EXPANSION	$50,000
2019	2019	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	003	3	9/23/2019	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $334,665

Issue Date FY: 2018 ( Subtotal = $303,750 )
2018	2018	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	001	2	8/29/2018	SUPPLEMENT FOR EXPANSION	$50,000
2018	2018	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	000	2	5/16/2018	NON-COMPETING CONTINUATION	$253,750
														Subtotal = $303,750

Issue Date FY: 2017 ( Subtotal = $217,500 )
2017	2017	NORTH DAKOTA STATE UNIVERSITY	1919 UNIVERSITY DR N, STE 102	FARGO	ND	58102	CASS	USA	Aging Research	000	1	9/6/2017	NEW	$217,500
														Subtotal = $217,500

Grand Total All Awards = $2,312,116

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

Award Number: R01AG056881

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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