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Tailor-Made Molecular Chaperones to Target Protein Misfolding

Award Number: R01AG082969
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Tailor-Made Molecular Chaperones to Target Protein Misfolding - Project Summary Numerous aging-associated neurodegenerative diseases are rooted in the misfolding of proteins and the generation of toxic protein aggregates, with Alzheimer's disease (AD) being the most prevalent form of dementia characterized by the aggregation of the amyloid beta peptide (Aβ) and hyperphosphorylated tau. Few effective strategies are currently available for most of these diseases. In this proposal, we will test the hypothesis that novel molecular chaperones can be evolved to recognize and target aggregation-prone proteins and ameliorate their associated toxicity, thus providing a new approach to intervene in protein misfolding diseases. Using Aβ as the model substrate, our specific goal is to provide proof-of-principle for a new platform for the directed evolution of molecular chaperones that can protect Aβ sequences from aggregation. The efficacy of the evolved chaperones in ameliorating Aβ toxicity will be tested in vitro and in vivo. The proposed studies will establish a new, facile, and broadly applicable approach to evolve novel molecular chaperones tailored to specific aggregation-prone target proteins and thus broadly impact diverse diseases rooted in protein misfolding. The evolved TMMCs are expected to achieve a specificity that is normally unattainable by other approaches, such as small molecules or general chaperone upregulation, and can supplement the reduced capacity of the cellular chaperone network during aging to protect neuronal cells from toxic protein aggregates.


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: 2025 ( Subtotal = $513,463 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Aging Research	000	3	7/11/2025	NON-COMPETING CONTINUATION	$513,463
														Subtotal = $513,463

Issue Date FY: 2024 ( Subtotal = $523,941 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Aging Research	000	2	4/26/2024	NON-COMPETING CONTINUATION	$523,941
														Subtotal = $523,941

Issue Date FY: 2023 ( Subtotal = $541,441 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Aging Research	000	1	8/4/2023	NEW	$541,441
														Subtotal = $541,441

Grand Total All Awards = $1,578,845

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Tailor-Made Molecular Chaperones to Target Protein Misfolding

Award Number: R01AG082969

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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