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Novel mechanism of HSF1-mediated neuroprotection

Award Number: R21NS084474
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2019

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Novel mechanism of HSF1-mediated neuroprotection - SUMMARY Enhanced activity of the heat shock factor-1 (HSF1) transcription factor has protective effects in a variety of tissue culture and in vivo models of protein aggregation-associated neurodegenerative disease. This neuroprotective effect of HSF1 is thought to be mediated through a stimulation of transcription of genes encoding heat shock proteins (HSPs). By acting as molecular chaperones the newly produced HSPs re-fold or help degrade misfolded proteins in cells that suffer thermal or proteotoxic stress. Stimulation of HSP gene transcription by HSF1 requires its homo-trimerization and binding to sequences called heat shock elements (HSEs) located mostly in the promoters of HSP genes. We recently demonstrated that HSF1 can protect neurons from both proteotoxic and non-proteotoxic death by a mechanism does not require its trimerization and is HSP-independent. The goal of this this proposal is to understand this novel HSP-independent mechanism of neuroprotection. We propose that HSF1 acts by binding to non-HSE sequences as a monomer and regulating genes unconnected to HSPs and other chaperones. We propose that neuroprotection by HSF1 through this non-canonical mechanism requires the activity of histone deacetylases (HDACs) and interaction with the Class III HDAC, SIRT1. The specific aims of our project are: The specific aims of our project are - Aim 1: To understand the role of histone deacetylases in HSF1-mediated neuroprotection. Aim 2: To identify genomic sequences bound by monomeric HSF1 using two separate approaches – ChiP- Seq and Bind-N-Seq. Aim 3: To identify genes regulated by monomeric HSF1 using RNA-Seq. Understanding the mechanism will lead to a better understanding of the process of neurodegeneration and provide the basis for the development of novel therapeutic approaches for neurodegenerative diseases.


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: 2020 ( Subtotal = -$78,520 )
2020	2017	SOUTHERN METHODIST UNIVERSITY	6425 BOAZ LANE	DALLAS	TX	75205	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2020	NON-COMPETING CONTINUATION	-$78,520
														Subtotal = -$78,520

Issue Date FY: 2017 ( Subtotal = $182,595 )
2017	2017	SOUTHERN METHODIST UNIVERSITY INC	6425 BOAZ	DALLAS	TX	75275	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/20/2017	NON-COMPETING CONTINUATION	$182,595
														Subtotal = $182,595

Issue Date FY: 2016 ( Subtotal = $231,017 )
2016	2016	SOUTHERN METHODIST UNIVERSITY	POST OFFICE BOX 750259	DALLAS	TX	75275	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/30/2016	NEW	$231,017
														Subtotal = $231,017

Grand Total All Awards = $335,092

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Novel mechanism of HSF1-mediated neuroprotection

Award Number: R21NS084474

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2019

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