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Role of serotonergic-activation of heat shock transcription factor in the regulation of age-related protein misfolding and toxicity in mammalian systems

Award Number: R21AG073416
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Role of serotonergic-activation of heat shock transcription factor in the regulation of age-related protein misfolding and toxicity in mammalian systems - ABSTRACT Protein misfolding is central to the pathology of the debilitating age-related diseases such as ALS, Alzheimer's, Parkinson's and Huntington's diseases that are increasing in our society today. Activating the heat shock transcription factor, HSF1, a transcription factor conserved across all kingdoms of life and responsible for the expression of molecular chaperones and other pro-survival gene products, results in a dramatic amelioration of the toxic effects of protein aggregation in animal models of proteinopathies. The activation of HSF1 was long understood to be an autonomous response of cells triggered by the increase in misfolded protein species. Yet, in tissues of patients suffering from the age-related neurodegenerative diseases, cells accumulate misfolded proteins but do not activate HSF1 to effectively counteract protein aggregation and toxicity. Thus, understanding how to activate HSF1 in situ could provide a powerful means to intervene in proteinopathies. Our recent studies have demonstrated that increases in the neuromodulator serotonin, acting through the G-protein coupled 5-HT4 receptor (5-HT4R), can activate HSF1 and increase molecular chaperone expression. Our preliminary data further show that serotonergic signaling is sufficient to decrease intracellular protein inclusions of polyQ expansion proteins in cultured mammalian cell models. Based on these exciting studies, we propose to test the hypothesis that modulating serotonergic signaling through 5-HT4R can protect against proteinopathies in a mouse model of Huntington's Disease by activating HSF1, and intend to dissect the intracellular mechanisms underlying such protection. If successful, our studies will establish a rational basis for exploring the role for 5-HT4R agonists in the protection against devastating neurodegenerative diseases of aging and provide evidence that serotonin-dependent changes in motivational state can modulate proteinopathies.


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: 2026 ( Subtotal = $0 )
2026	2022	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Aging Research	000	3	3/26/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Aging Research	001	3	3/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2022	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Aging Research	000	2	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $9,277 )
2024	2022	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Aging Research	000	2	2/21/2024	NON-COMPETING CONTINUATION	-$75,457
2024	2022	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Aging Research	001	3	2/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$84,734
														Subtotal = $9,277

Issue Date FY: 2022 ( Subtotal = $193,464 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Aging Research	000	2	5/23/2022	NON-COMPETING CONTINUATION	$193,464
														Subtotal = $193,464

Issue Date FY: 2021 ( Subtotal = $245,724 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Aging Research	000	1	9/1/2021	NEW	$245,724
														Subtotal = $245,724

Grand Total All Awards = $448,465

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Role of serotonergic-activation of heat shock transcription factor in the regulation of age-related protein misfolding and toxicity in mammalian systems

Award Number: R21AG073416

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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