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Novel mechanisms of muscle and bone loss with HIV infection, antiretroviral therapy, and aging.

Award Number: R01AR082307
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Novel mechanisms of muscle and bone loss with HIV infection, antiretroviral therapy, and aging. - Our proposal is in direct response to the special Funding Opportunity Announcement (FOA) PAR-21-068 “Multidisciplinary Studies of HIV/AIDS and Aging (R01)”. A frailty phenotype is frequently observed in HIV patients on long term antiretroviral therapy (ART), and both osteoporosis and sarcopenia are now recognized as co-morbidities among older people with HIV. Loss of muscle mass and strength are in turn associated with poor health outcomes ranging from falls and fractures to accelerated disease progression and increased mortality. Our goal is to address this problem by providing critical, new information on the cellular and molecular mechanisms underlying musculoskeletal dysfunction with HIV infection and ART, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Recent studies identify the aryl hydrocarbon receptor (AhR) as playing a key role in regulating organismal aging and lifespan. Our group has found that AhR activation can induce senescence in bone marrow stem cells, and others have observed that AhR overexpression induces muscle atrophy. Uniting these observations, our central hypothesis is that muscle- and bone-specific AhR activation are key drivers of muscle and bone loss in patients with HIV on ART. Our preliminary data provide a strong rationale for this hypothesis and indicate that 1) markers of muscle atrophy, bone loss, and AhR activation are increased in our mouse model of HIV infection, 2) AhR is highly expressed in muscle and bone, and targeted knockout of AhR in these tissues increases lean mass and trabecular bone mass, 3) pharmacological inhibition of AhR increases muscle strength and markers of bone formation in mice, and 4) the antiretroviral emtricitabine (FTC) increases AhR activation and senescence in muscle cells and these effects are attenuated by AhR silencing. Specific Aim 1 tests the hypothesis that AhR activation is a key factor driving muscle and bone loss with aging and HIV infection. Specific Aim 2 tests the hypothesis that AhR activation is a key factor driving muscle and bone loss with aging and antiretroviral therapy. Our expected outcomes include 1) defining the role of AhR in skeletal muscle and bone with HIV infection and ART so that it can be targeted therapeutically, and 2) characterizing the impact of aging and ART on AhR activation in skeletal muscle and bone. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of HIV- and age-induced pathologies. Ultimately, these data will enable clinicians to improve disease outcomes and, consequently, public health.


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: 2025 ( Subtotal = $576,322 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/10/2025	NON-COMPETING CONTINUATION	$576,322
														Subtotal = $576,322

Issue Date FY: 2024 ( Subtotal = $621,147 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/7/2024	NON-COMPETING CONTINUATION	$44,825
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/20/2024	NON-COMPETING CONTINUATION	$576,322
														Subtotal = $621,147

Issue Date FY: 2023 ( Subtotal = $640,358 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/23/2023	NEW	$640,358
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	4/21/2023	NEW	$0
														Subtotal = $640,358

Grand Total All Awards = $1,837,827

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Novel mechanisms of muscle and bone loss with HIV infection, antiretroviral therapy, and aging.

Award Number: R01AR082307

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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