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Chronic Stress, Glucocorticoids, and Progesterone in Brain Aging

Award Number: R01AG037868
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Chronic Stress, Glucocorticoids, and Progesterone in Brain Aging - Evidence indicates that prolonged/ repeated behavioral stress promotes brain aging. This is thought to be due, at least in part, to stress associated glucocorticoid (GC) secretion, which in turn binds to glucocorticoid receptors, exerting transcriptional and other effects. A key downstream mediator in this signaling pathway, serum-and- glucocorticoid kinase 1 (Sgk1) accelerates, and the female sex steroid progesterone (P4) blunts, the effects of GCs. However, despite the negative clinical consequences of chronic stress exposure with aging and/or in female subjects, little work has examined how aging may change the stress response, the mechanisms through which stress may accelerate brain aging, the degree to which stress-accelerated aging is dependent on GC, is driven by Sgk1, or is inhibited by P4. Our preliminary data suggests that hippocampal Sgk1 is upregulated by aging, stress, and GCs in white matter oligodendrocytes, and that the female sex hormone progesterone (P4) blunts the effects of stress/GCs and may serve as an endogenous protectant that is lost with age in females. To address these knowledge gaps, we propose 3 aims to investigate: the age-course of the response to chronic stress or chronic GCs in males and females; whether viral overexpression of Sgk1 exacerbates, or systemic P4 administration ameliorates, stress-accelerated aging; and whether the pharmacologic sensitivity of hippocampal tissue to GC and P4 is shifted with age or chronic stress/GC. Cognitive and anxiety-related behavior, blood hormone measures, and a novel panel of 205 hippocampal genes that are robustly changed with aging across multiple studies, will be used to test for stress/GC-accelerated aging and intervention effects, as will downstream gray and white matter Sgk1 expression and microglial response to microinjury- two processes demonstrated to be glucocorticoid sensitive and exaggerated in white vs. gray matter in preliminary data. Thus, the proposed studies will yield essentially the first comprehensive test of the hypothesis that chronic stress accelerates transcriptional brain aging and will illuminate sex differences in stress responsiveness and the potential roles of GC, P4, and Sgk1 in gray and white matter. Even if all of our working hypotheses are rejected by the results, the proposed studies should have translational value for geriatric medicine.


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: 2027 ( Subtotal = -$13,093 )
2027	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	10	10/13/2026	NON-COMPETING CONTINUATION	-$13,093
														Subtotal = -$13,093

Issue Date FY: 2025 ( Subtotal = $386,519 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	10	6/13/2025	NON-COMPETING CONTINUATION	$31,553
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	10	4/9/2025	NON-COMPETING CONTINUATION	$354,966
														Subtotal = $386,519

Issue Date FY: 2024 ( Subtotal = $394,406 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	9	5/14/2024	NON-COMPETING CONTINUATION	$394,406
														Subtotal = $394,406

Issue Date FY: 2023 ( Subtotal = $394,406 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	8	5/10/2023	NON-COMPETING CONTINUATION	$394,406
														Subtotal = $394,406

Issue Date FY: 2022 ( Subtotal = $394,406 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	7	6/16/2022	NON-COMPETING CONTINUATION	$394,406
														Subtotal = $394,406

Issue Date FY: 2021 ( Subtotal = $394,406 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	6	9/14/2021	COMPETING CONTINUATION	$394,406
														Subtotal = $394,406

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	5	5/23/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $294,159 )
2015	2015	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Aging Research	000	5	2/27/2015	NON-COMPETING CONTINUATION	$294,159
														Subtotal = $294,159

Issue Date FY: 2014 ( Subtotal = $303,343 )
2014	2014	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Aging Research	000	4	2/21/2014	NON-COMPETING CONTINUATION	$303,343
														Subtotal = $303,343

Issue Date FY: 2013 ( Subtotal = $286,735 )
2013	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Aging Research	000	3	4/4/2013	NON-COMPETING CONTINUATION	$273,081
2013	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Aging Research	001	3	5/17/2013	NON-COMPETING CONTINUATION	$13,654
														Subtotal = $286,735

Issue Date FY: 2012 ( Subtotal = $303,497 )
2012	2012	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Aging Research	000	2	2/23/2012	NON-COMPETING CONTINUATION	$303,497
														Subtotal = $303,497

Issue Date FY: 2011 ( Subtotal = $303,566 )
2011	2011	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Aging Research	000	1	2/17/2011	NEW	$303,566
														Subtotal = $303,566

Grand Total All Awards = $3,442,350

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Chronic Stress, Glucocorticoids, and Progesterone in Brain Aging

Award Number: R01AG037868

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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