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Role of IL-32 as a predictor and mediator of Premature Aging Phenotypes(PAP) in HIV infection.

Award Number: R01AG054324
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Role of IL-32 as a predictor and mediator of Premature Aging Phenotypes(PAP) in HIV infection. - PROJECT SUMMARY People living with HIV (PLWH) are aging and have increased risk for age-associated health complications such as cardiovascular diseases (CVDs) and low bone mineral density. Both CVD and decreased bone mineral density accelerate frailty, which is a complex of geriatric conditions underlying biological vulnerability and decreased physiological competence that results in multiple adverse outcomes. Inflammation plays a critical role in these ageassociated phenotypes. Identification of novel surrogate inflammatory biomarkers with inherent potential as disease causative agents not only enhances risk stratification in the aging HIV+ populating but also offers important cues for novel therapeutic strategies. IL-32 is a multi-isoform proinflammatory cytokine that we showed to be linked with CVD and aging in HIV infection and is negatively regulated by the gut short chain fatty acid caproic acid. IL-32 is also involved in mechanisms governing bone metabolism, mechanisms that are potentially involved in atherosclerosis. Here, we hypothesize that in HIV infection, IL-32 is involved in Premature Aging Phenotypes (PAP) that are manifested by CVD, altered body composition (low bone mineral density and abnormal fat deposition) and frailty. To validate this hypothesis, our current applications proposes an approach combining in vivo cardiovascular imaging, ex vivo measures of IL- 32 from PLWH for whom frailty and body composition data are available, and in vitro studies intending to investigate the mechanistic link between IL-32 expression and PAP. In Aim 1, we will study the expression of IL-32 isoforms in peripheral blood in PLWH in two large cohorts of men and women; the Canadian HIV and Aging Cohort Study (CHACS) and the Women's Interagency HIV Cohort Study (WIHS), now combined with the Multicenter AIDS Cohort Study (MACS) in the MWCCS cohort, respectively. We will evaluate the potential of IL-32 isoforms in predicting PAP in these two cohorts using two types of analysis; a binary analysis (presence/absence of CVD, frailty and osteoporosis) and joint occurrence of the adverse phenotypes. In Aim 2, we will investigate the mechanisms by which caproic acid regulates IL-32 expression in 3 major cell types; intestinal epithelial cells (as a primary cell types expected to be exposed to caproic acid in gut), CD4 T cells (major cells producing IL-32 and main reservoir for latent HIV under ART) and primary vascular endothelial cells, the dysfunction of which results in frank atherosclerosis. In Aim 3, we further propose to dissect the mechanism(s) by which the CVD-associated IL-32 isoforms impact the process of osteoclastogenesis (differentiation of osteoclast cells involved in bone resorption, lower mineral bone density and potentially the development of noncalcified atherosclerotic lesions). Together, the overarching goal of this project is to demonstrate that IL-32 is a central player in systemic inflammation and an accelerator of multiple aging phenotypes (CVD, frailty and osteoporosis) and that this cytokine can be used as a predictive biomarker for PAP and also as a therapeutic target.


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 = $427,996 )
2024	2024	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTRAAL	QC			CAN	Aging Research	000	8	5/23/2024	NON-COMPETING CONTINUATION	$427,996
														Subtotal = $427,996

Issue Date FY: 2023 ( Subtotal = $433,719 )
2023	2023	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ			CAN	Aging Research	001	7	5/10/2023	NON-COMPETING CONTINUATION	$433,719
2023	2020	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTRAAL	QC			CAN	Aging Research	000	5	4/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $433,719

Issue Date FY: 2022 ( Subtotal = $439,372 )
2022	2022	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ			CAN	Aging Research	000	6	7/27/2022	COMPETING CONTINUATION	$439,372
														Subtotal = $439,372

Issue Date FY: 2020 ( Subtotal = $438,200 )
2020	2020	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Aging Research	000	5	6/29/2020	NON-COMPETING CONTINUATION	$438,200
														Subtotal = $438,200

Issue Date FY: 2019 ( Subtotal = $399,411 )
2019	2019	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Aging Research	000	4	6/1/2019	NON-COMPETING CONTINUATION	$399,411
														Subtotal = $399,411

Issue Date FY: 2018 ( Subtotal = $434,974 )
2018	2018	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	850 RUE SAINT-DENIS	MONTREAL	PQ	H2X 0A9		CAN	Aging Research	000	3	6/14/2018	NON-COMPETING CONTINUATION	$434,974
														Subtotal = $434,974

Issue Date FY: 2017 ( Subtotal = $395,625 )
2017	2017	CENTRE HOSPITALIER DE L'UNIVERSITE DE MONTREAL	3840 RUE SAINT-URBAIN	MONTREAL	PQ	H2W 1T8		CAN	Aging Research	000	2	7/5/2017	NON-COMPETING CONTINUATION	$395,625
														Subtotal = $395,625

Issue Date FY: 2016 ( Subtotal = $433,867 )
2016	2016	UNIVERSITY OF MONTREAL HOSPITAL	3840 ST URBAIN STREET	MONTREAL, QUEBEC				CAN	Aging Research	000	1	9/27/2016	NEW	$433,867
														Subtotal = $433,867

Grand Total All Awards = $3,403,164

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Role of IL-32 as a predictor and mediator of Premature Aging Phenotypes(PAP) in HIV infection.

Award Number: R01AG054324

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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