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J-domain protein conformational selectivity for tau in disease

Award Number: R01AG078888
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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J-domain protein conformational selectivity for tau in disease - Tau is a microtubule-associated protein that converts from a healthy shape into beta-sheet rich amyloid structures which underlie pathology in Alzheimer’s disease and over 20 other related tauopathies. Recent cryo- EM structures of tau fibrils derived from different tauopathy patient samples reveal structural polymorphisms that link each tauopathy to distinct amyloid structures. The J-domain protein (JDP) molecular chaperone family play a central role in regulating tau function to mitigate amyloid assembly in disease. How the diverse family of JDP molecular chaperones discriminate binding different tau conformations remains poorly understood. My lab employed a CRISPR knock-out screen for factors that regulate tau aggregation and identified two JDPs, DnaJC7 and DnaJB6. In recently published worked, we revealed that DnaJC7 has enhanced specificity for natively folded wild-type tau compared to aggregation-prone mutants or pathogenic seeds. We hypothesize that the diverse JDP family encodes selectivity for different conformations of substrates. Our data suggests that novel mechanisms of JDP regulation of tau aggregation could be exploited as both a diagnostic and a therapeutic intervention. Several important questions remain. How do JDPs that bind to tau discriminate different tau conformations? Can JDPs modify tau pathology in vivo? In this proposal, we aim to define how a subset of JDPs recognize different conformations of tau linked to different tau pathologies in cells, in vitro and in vivo. We will first use biochemical and cellular approaches to understand how JPDs recognize different conformations of tau. We will also determine structures of tau in complex with DnaJC7 and DnaJB6. Finally, we will test the activity of DnaJC7 and DnaJB6 on the development of tau pathology in vivo. Our long-term goal is to develop therapies that can reduce amyloid deposition and slow neurodegeneration. This project is in alignment with the mission of the NIA to support biological and clinical research on aging.


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 = $401,800 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Aging Research	000	2	8/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$401,800
														Subtotal = $401,800

Grand Total All Awards = $401,800

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J-domain protein conformational selectivity for tau in disease

Award Number: R01AG078888

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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