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Sirt-1-mediated regulation of NeuroAIDS

Award Number: R21AG054240
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2019

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Sirt-1-mediated regulation of NeuroAIDS - Sirt-1-mediated regulation of NeuroAIDS In the post anti-retrovirals (ART) era, human immunodeficiency virus (HIV) infection is no longer a deadly condition. Rather, HIV+ individuals age with the chronic infection. Therefore, the consequences of HIV infection overlap and synergize with normal senescence in various organs, especially the brain. It is accepted that HIV infection triggers in the Central Nervous System (CNS) several hallmarks of aging, such as cognitive and motor disorders and dementia, regardless of CD4 levels1. However, the molecular aspects underlining this accelerated aging process in HIV-infected brains are poorly understood. Here, using the non-human primate model of neuroAIDS, SIV infection of rhesus macaques, we will provide preliminary evidence that the infection triggers molecular markers that were previously associated to aging in humans. We propose to explore the hypothesis that the virus causes a disruption of an epigenetic pathway that regulates aging and lifespan, which can be responsible for enhancing molecules that aggravate the inflammatory phenotype associated with CNS functional decay, ultimately represented by encephalitis. In this proposal we will address an important problem of how HIV promotes a rapid aging of the brain though a potential dysregulation of transcription, centered and orchestrated by the levels and function of Sirt-1, which is a molecule with profound implications to lifespan and in aging models. We studied the dynamics of Sirt-1 binding to chromatin in microglia from control and SIV-infected macaques, and identified a network of genes regulated by Sirt-1. Narrowing our analysis to in-promoter Sirt-1 binding sites, we generated a list of molecules that may have a critical role in the development of an inflammatory phenotype in the brain. In this application, we aim at examining the role of this network of molecules in depth, integrating CNS dysfunction and age, to understand the molecular and mechanistic basis for deep changes in the inflammatory environment that are common to aging and to HIV infection, and that synergize to aggravate neurological syndromes, even in the post- ART era.


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: 2020 ( Subtotal = $0 )
2020	2019	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	3	4/11/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $237,750 )
2019	2019	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	3	11/15/2018	NON-COMPETING CONTINUATION	$237,750
														Subtotal = $237,750

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	12/8/2017	NEW	-$288,000
2018	2017	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	001	2	12/8/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$288,000
2018	2017	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	003	2	2/21/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,250
2018	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	002	1	2/21/2018	NEW	-$2,250
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $290,250 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	1	8/22/2017	NEW	$0
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	8/21/2017	NEW	$290,250
														Subtotal = $290,250

Grand Total All Awards = $528,000

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Sirt-1-mediated regulation of NeuroAIDS

Award Number: R21AG054240

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2019

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