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Metabolic Regulation of Protein Folding Homeostasis

Award Number: R35GM162857
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/11/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Metabolic Regulation of Protein Folding Homeostasis - ABSTRACT: Disruptions in the cellular processes that maintain protein homeostasis (proteostasis) through the regulation of protein synthesis, folding, and degradation contribute to the pathophysiology of numerous human diseases, including cardiovascular disorders, metabolic diseases, and neurodegeneration. These proteostasis- linked conditions are often comorbidities, suggesting that dysfunctional proteostasis in one tissue can predispose other tissues to pathologic proteostasis disruptions. The systemic nature of these disorders highlights the urgent need for research into the mechanisms that govern inter-cellular and inter-tissue proteostasis communication in order to develop more effective therapies for these disorders. Proteostasis is maintained at the cellular level through the tightly controlled activation of stress responsive signaling pathways, such as the heat shock response (HSR). The HSR responds to proteostasis disruptions in the cytosol primarily by activating the transcription factor HSF1. This activation leads to increased expression of cytosolic protein chaperones, thereby increasing the protein folding capacity of the cell. Intriguingly, several model organisms exhibit non-autonomous coordination of HSF1 activity, suggesting that the folding capabilities of a cell can be influenced by remote cells or tissues. However, the mechanism(s) by which HSR activity is regulated across cells and tissues is poorly understood - especially in mammalian systems. Cytosolic proteins regulated by HSF1 are generally not secreted, making them unlikely candidates for coordinating proteostasis between tissues. Intriguingly, recent studies have shown that HSF1 also regulates the expression of enzymes involved in cellular metabolism and that its activity can alter the levels of cellular metabolites. We hypothesize that the export of these metabolites through physiologic mechanisms influences the proteostasis of distal tissues, such as the central nervous system (CNS). This inter-tissue signaling mechanism could then support the restoration of proteostasis at the cells or tissue of origin through alterations in trophic factors or behaviors. Our work tests our hypothesis by establishing a role for HSF1 in modulating the synthesis of a circulating non-proteinogenic amino acid both in vitro and in vivo. We show that this metabolite is intricately involved in mediating HSR activity in the brain, particularly in neurons. Using a combination of chemical-genetic and pharmacologic approaches, we then define the impact of the HSF1-mediated metabolite on neuronal proteostasis and functions. Finally, we identify additional HSF1-regulated metabolites produced in donor tissues which alter neuronal proteostasis. Through these efforts, we describe a new HSR-mediated signaling paradigm that effectively coordinates cytosolic proteostasis across distal tissues. Understanding these inter-tissue signaling networks offers new insights for developing therapies that both treat individual proteostasis-related diseases and address the systemic nature of these conditions. By targeting these communication networks, we aim to develop more effective treatments for pathologies caused by dysregulated proteostasis.


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 = $410,169 )
2026	2026	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	8/11/2026	NEW	$410,169
														Subtotal = $410,169

Grand Total All Awards = $410,169

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Metabolic Regulation of Protein Folding Homeostasis

Award Number: R35GM162857

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/11/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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