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Endogenous steroid hormones as mediators of interorgan communication with the musculoskeletal system

Award Number: U01AG086158
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Endogenous steroid hormones as mediators of interorgan communication with the musculoskeletal system - Project Summary/Abstract: Glucocorticoids (GC) are multisystem essential hormones, highlighted by the fact that nearly every tissue in the body expresses glucocorticoid receptors (GR). Although released from the adrenal glands in a hormonal fashion, GC levels are regulated at the tissue level in a paracrine manner by conversion enzymes such as Hsd11b1 and Hsd11b2. While the detrimental effects of exogenous pharmacological doses of GC are well known, the roles for endogenous, adrenal-derived, physiological concentrations of GC are poorly understood, particularly in musculoskeletal aging. Endogenous GC are known to be dysregulated in aging: in older humans and mice, circulating GC levels increase, lose proper circadian cycling, and show amplified local conversion to active forms via expression of enzymes like Hsd11b1 with age in bone. Given the adverse effects of exogenous GC on the skeleton, we originally predicted that deletion of the GR would protect the skeleton from aging-induced bone loss. However, the opposite was surprisingly true: conditional loss of GR in Osx-expressing cells promoted low bone mass, osteoblast dysfunction, and increased bone marrow adipose tissue (BMAT) in young adult mice that worsened in old mice. As a possible explanation for this finding, GC also bind to the mineralocorticoid receptor (MR), and do so with higher affinity than to GR. Our preliminary data support a paradigm shift where accelerated skeletal aging could be occurring through aberrant MR expression or via failure of GC bio-protective mechanisms (e.g., excessive Hsd11b1 GC activation without counterbalance from Hsd11b2 activity). Our published studies also show that conditional loss of GR in Osx-expressing cells causes systemic changes suggestive of bone-mediated interorgan communication (IOC) in aged mice including low muscle mass, low physical activity, and increased fat despite no loss of GR tissues outside of bone. Our preliminary data suggest that GC-activated MR is a novel but untested mediator of bone-initiated IOC in aging evident in this model. We have developed inducible Osx-targeted MR conditional knockout and MR overexpressing mouse models, and an inducible Osx-targeted conditional knockout mouse model of Hsd11b1. We will leverage these novel animal models to test the contribution of local GC activation and signaling through the MR within the skeletal niche to mechanisms of bone aging and IOC. Our goal is to determine the molecular mechanisms and causal role of adrenal-derived endogenous GC in the development of an aging phenotype in bone, BMAT, and IOC with peripheral tissues like skeletal muscle and fat. We propose that disrupted IOC from abnormal bone MR expression or activation results in accelerated tissue aging. MR inhibitors such as eplerenone are used clinically for the regulation of blood pressure, presenting a unique opportunity for drug repurposing to improve musculoskeletal function with age and thus address a major clinical problem. Successful completion of this research will significantly advance understanding of fundamental pathways in the biology of musculoskeletal aging and will identify new therapeutic targets for preventing frailty with age.


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: 2026 ( Subtotal = $470,599 )
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	3	1/26/2026	NON-COMPETING CONTINUATION	$427,225
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	3	1/30/2026	NON-COMPETING CONTINUATION	-$3,685
2026	2026	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	002	3	2/25/2026	NON-COMPETING CONTINUATION	$47,059
														Subtotal = $470,599

Issue Date FY: 2025 ( Subtotal = $465,220 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	2	1/27/2025	NON-COMPETING CONTINUATION	$427,243
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	2	8/12/2025	NON-COMPETING CONTINUATION	$37,977
														Subtotal = $465,220

Issue Date FY: 2024 ( Subtotal = $467,028 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	1	5/13/2024	NEW	$467,028
														Subtotal = $467,028

Grand Total All Awards = $1,402,847

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Endogenous steroid hormones as mediators of interorgan communication with the musculoskeletal system

Award Number: U01AG086158

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 05/15/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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