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Mechanisms of misfolded protein sequestration and degradation

Award Number: R15GM163286
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: 05/22/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Mechanisms of misfolded protein sequestration and degradation - Project Summary/Abstract Misfolded proteins acquire toxic conformations that disrupt essential cellular processes, leading to cell death in diseases like cancer, Alzheimer’s, Parkinson’s, and Huntington’s diseases. Therefore, cells have developed different ways to manage misfolded proteins. This research will elucidate how cells sort misfolded proteins into distinct compartments that sequester and concentrate toxic, misfolded proteins for more efficient refolding or clearance. The quality control mechanisms that manage misfolded proteins wear down over time. This results in the buildup of protein aggregates that are a hallmark of proteinopathies. Identifying novel mechanisms for how cells sort misfolded proteins into quality control compartments will create numerous new therapeutic strategies to treat these devastating disorders. Previous work has shown that misfolded proteins are spatially sequestered into membrane-less compartments in the cell. However, we don’t know the mechanisms that control the formation, localization, and degradation of these compartments. This knowledge gap is even larger for aggregation-prone proteins such as those that cause disease. We will address the fundamental questions of why and how cells form inclusions, the role of inclusions in disease, and critically, how to promote degradation of these inclusions to prevent cell death in disease. These studies can also shed light on the apparent paradox of protein aggregates being both toxic and protective to cells. Our recent work elucidated a potential mechanism of degradation as compartments are recruited to the nucleus- vacuole junction (NVJ) to facilitate vacuolar clearance. ESCRT proteins, normally associated with protein trafficking, play an important role in this novel clearance mechanism. We are using a panel of misfolded proteins to probe the interactions required for sorting misfolded proteins into protein quality control compartments, transporting compartments to specific cellular sites, and determining clearance mechanisms for the compartments. We will accomplish this by using a combination of genetic deletions, live-cell time-lapse fluorescence microscopy, and a suite of biochemical techniques for determining changes in the aggregation state of proteins previously developed by the PI. The overall goal of our research is to uncover the basic cellular mechanisms that go awry in proteinopathies such as cancer and neurodegeneration.


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 = $569,258 )
2026	2026	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Biomedical Research and Research Training	000	1	5/20/2026	NEW	$569,258
														Subtotal = $569,258

Grand Total All Awards = $569,258

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Mechanisms of misfolded protein sequestration and degradation

Award Number: R15GM163286

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: 05/22/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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