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Molecular and in vivo Determinants of p66Shc-Mediated ROS Function in Cardiovascular Health

Award Number: F30HL149279
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/24/2019
PERIOD OF PERFORMANCE END DATE: 09/23/2023

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Molecular and in vivo Determinants of p66Shc-Mediated ROS Function in Cardiovascular Health - Project Summary: p66Shc is a ShcA family member whose reactive oxygen species (ROS) production and cytochrome c (cyt c) interactions impact cardiovascular pathologies including ischemia/reperfusion injuries, endothelial dysfunction, and coronary artery disease (CAD). ShcA ROS affects CAD and stroke strongly enough that its levels can predict stroke severity or determine CAD presence in patients. Although inhibiting or removing other ROS producing proteins is fatal in mice, p66Shc knockouts are beneficial, without physiological detriments or increased compensatory ROS. The Hays lab is the first to produce full-length p66Shc, putting my project in a unique position to: 1) define the mechanism of ROS production 2) validate in vitro mechanistic findings with an in vivo model by illustrating how mechanistic manipulation can benefit pathology 3) understand how p66Shc structure mediates ROS generation and cyt c interactions. Preliminary data show that p66Shc contains four intramolecular disulfide bonds involved in producing ROS, independent of metals or cofactors. To define the mechanism, I will: 1) use Danio rerio (zebrafish) human transgenic p66Shc mutants that increase or decrease ROS production, or change p66Shc localization signals in vitro as well as p66Shc knockouts to analyze post-MI wound healing rate in relation to ROS production and p66Shc localization (increased p66Shc ROS or mitochondrial localization is associated with worse outcomes) 2) determine the order in which specific cysteines pass electrons between domains during thiol disulfide exchange 3) identify physiologically relevant initial electron donor(s) that enable ROS production. I will achieve this by performing cryoinjury of zebrafish with various p66Shc genotypes, cysteine mutagenesis combined with superoxide sensitive mass spectroscopy studies, and measuring ROS produced from potential electron donors in an oxygen free environment, respectively. My project will directly impact cardiovascular disease by identifying mechanistic and structural therapeutic targets that can affect clinical outcomes for ROS-mediated pathology. Previous studies with the isolated CH2 domain, thought to be responsible for p66Shc ROS function, indicate that the CH2 domain oxidizes cyt c to generate ROS (thermodynamically unfavorable). My full-length p66Shc and isolated CH2 domain studies show that they reduce cyt c, produce ROS independent of cyt c, and inhibit cyt c's cardiolipin-induced peroxidase activity. Cyt c peroxidase inhibition is a thermodynamically acceptable explanation for the increased ROS in the aforementioned studies. I will define the structural basis and conformational dynamics of these interactions by testing p66Shc and its CH2 domain for cyt c binding, ROS activity, and by performing Hydrogen-Deuterium exchange analysis. Lastly, I will optimize the conditions currently producing 5 Å diffractable crystals to solve the first full-length structure of the ShcA family, p66Shc.


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: 2024 ( Subtotal = -$43,887 )
2024	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	7/24/2024	NON-COMPETING CONTINUATION	-$43,887
														Subtotal = -$43,887

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	8/23/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	3	8/19/2021	NON-COMPETING CONTINUATION	$51,036
														Subtotal = $51,036

Issue Date FY: 2020 ( Subtotal = $40,893 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	2	8/19/2020	NON-COMPETING CONTINUATION	$40,893
														Subtotal = $40,893

Issue Date FY: 2019 ( Subtotal = $40,389 )
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	001	1	9/1/2019	NEW	$0
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	1	9/1/2019	NEW	$40,389
														Subtotal = $40,389

Grand Total All Awards = $140,183

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Molecular and in vivo Determinants of p66Shc-Mediated ROS Function in Cardiovascular Health

Award Number: F30HL149279

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/24/2019

PERIOD OF PERFORMANCE END DATE: 09/23/2023

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