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Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

Award Number: R01HL142216
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes - This Administrative Supplement is in response to NOT-AG-20-034, entitled ‘Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease’. The overall goal of this supplement is to use our existing award, focused on how diabetes-dependent disruption of the circadian clock contributes to the adverse effects of diabetes on the heart, as the platform to assess the impact of these factors on Alzheimer’s disease (AD) and its related dementias (ADRD). The parent application tests the hypothesis that changes in the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) during diabetes impairs circadian regulation of autophagy/mitophagy in cardiac dysfunction. Interestingly, circadian dysregulation, diabetes, perturbation of protein O-GlcNAcylation, mitochondrial dysfunction and autophagy/mitophagy have also all been linked to AD. It is currently unknown whether 1) O-GlcNAcylation, mitophagy, and mitochondrial function in the brain are circadian regulated and affected by diabetes; and 2) whether circadian, O-GlcNAc and mitophagy manipulations change cognition and neuropathology. Thus our current supplement application will test the hypothesis that AD and ADRD related neurological and pathological phenotypes are a consequence of dysregulation of the circadian clock-O-GlcNAcylation axis resulting in impaired neuronal mitophagy and bioenergetics that is exacerbated by T2DM. The same mouse genetic and pharmacological manipulations, parallel histology and biochemical methods will be used in the brain in the supplement project, as described in the parent project. We will perform studies with the following 2 aims: 1) Determine whether the circadian regulation of O-GlcNAcylation, mitophagy and mitochondrial function in the brain, as well as cognition and neuropathology, are affected by diabetes; and 2) Determine whether genetic perturbation of mitophagy, pharmacological enhancement of mitophagy, and pharmacological perturbation of circadian clock affect O-GlcNAcylation, mitophagy, mitochondrial function, cognition and neuropathology. The goal is to gain new fundamental insights into aspects of circadian disruption and diabetes in the pathogenesis of AD, which have not been investigated previously. New insights gained from this study will help identify innovative approaches for alleviating cognitive and neuropathological deficits in AD.


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 = -$50,386 )
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	12/1/2023	NON-COMPETING CONTINUATION	-$28,440
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	4	12/1/2023	SUPPLEMENT FOR EXPANSION	-$21,946
														Subtotal = -$50,386

Issue Date FY: 2021 ( Subtotal = $852,369 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	1/21/2021	NON-COMPETING CONTINUATION	$433,006
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	4	4/13/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	4	4/9/2021	SUPPLEMENT FOR EXPANSION	$371,250
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	003	4	5/19/2021	NON-COMPETING CONTINUATION	$48,113
														Subtotal = $852,369

Issue Date FY: 2020 ( Subtotal = $481,119 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	3/7/2020	NON-COMPETING CONTINUATION	$24,056
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	1/1/2020	NON-COMPETING CONTINUATION	$457,063
														Subtotal = $481,119

Issue Date FY: 2019 ( Subtotal = $481,119 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	1/10/2019	NON-COMPETING CONTINUATION	$481,119
														Subtotal = $481,119

Issue Date FY: 2018 ( Subtotal = $481,119 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	4/9/2018	NEW	$481,119
														Subtotal = $481,119

Grand Total All Awards = $2,245,340

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Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

Award Number: R01HL142216

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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