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Epigenetic mechanisms of stress and age-related cognitive decline

Award Number: K01AG061263
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Epigenetic mechanisms of stress and age-related cognitive decline - Project Summary/Abstract. Dysfunction of the hypothalamic-pituitary-adrenal axis, the major neuroendocrine system regulating physiological responses to stress, is a common feature of older individuals with memory loss, including those with Alzheimer’s disease. Indeed, accumulating effects of stress and glucocorticoid exposure across the lifespan are presumed to contribute to age-related memory loss and enhance susceptibility to Alzheimer’s disease via deleterious signaling alterations in glucocorticoid receptor-expressing neurons residing in the medial temporal and frontal lobes that support normal memory. Neural activity in the hippocampus, which supports declarative memory, or the prefrontal cortex, a region that is indispensable for working memory, requires a fine balance between persistent excitation of glutamatergic, pyramidal neurons and competitive inhibition provided by GABAergic interneurons. Recently published and preliminary findings from our laboratory indicate that memory loss observed in aging or following chronic stress is mechanistically linked to altered signaling via ionotropic NMDA receptors and metabotropic GABAB receptors in these brain regions. These similarities suggest a common mechanism contributes to memory loss in chronic stress and aging and, by extension, stress may interact with aging to increase severity of memory loss and susceptibility to age-related neurodegenerative disease. Our long-term goal is to understand the molecular mechanisms that translate stressful experiences into lasting changes in neural function that contribute to memory loss across the full lifespan and, in so doing, identify new targets that will lead to the development of therapeutics that protect or restore memory in older individuals. This project will use a rat model of age-related memory loss to test the hypotheses that 1) stress increases vulnerability to memory loss across the lifespan via DNA methylation that durably modifies transcriptional activity of genes that encode for synaptic proteins and 2) that stress-dependent molecular changes in the aged brain require signaling transduced by glucocorticoid and mineralocorticoid receptors. Such findings would be significant because they will identify specific molecular bases that transform experiential and physiological factors into impaired synaptic function and memory loss in later life and also establish a critical foundation for developing new therapeutic approaches to both prevent and reverse age- related memory loss. This proposal builds on the applicant’s long-standing scientific commitment to investigate the neural basis for cognitive decline in aging and Alzheimer’s disease. Productive collaborations initiated in a prior F32 award will be advanced and combined with new mentorship, affording significant technical and conceptual training in cutting-edge molecular approaches and bioinformatics. The scientific knowledge, technical competence, professional skills and original data cultivated under this K01 award will directly support the applicant’s transition to an independent scientific career as a PI leading his own NIH-funded research program.


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 = $0 )
2024	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	5	5/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $122,259 )
2023	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	5	5/5/2023	NON-COMPETING CONTINUATION	$122,259
														Subtotal = $122,259

Issue Date FY: 2022 ( Subtotal = $119,327 )
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	4	5/25/2022	NON-COMPETING CONTINUATION	$119,327
														Subtotal = $119,327

Issue Date FY: 2021 ( Subtotal = $116,482 )
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	3	3/17/2021	NON-COMPETING CONTINUATION	$116,482
														Subtotal = $116,482

Issue Date FY: 2020 ( Subtotal = $113,590 )
2020	2020	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	001	2	7/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$113,590
2020	2020	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	003	2	9/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$80,476
2020	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	1	7/1/2020	NEW	$0
2020	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	002	1	9/17/2020	NEW	-$80,476
														Subtotal = $113,590

Issue Date FY: 2019 ( Subtotal = $110,523 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	1	3/29/2019	NEW	$110,523
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	001	1	4/15/2019	NEW	$0
														Subtotal = $110,523

Grand Total All Awards = $582,181

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Epigenetic mechanisms of stress and age-related cognitive decline

Award Number: K01AG061263

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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