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HIV-1 and amyloid beta interactions at the blood-brain barrier

Award Number: R01MH072567
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2005
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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HIV-1 and amyloid beta interactions at the blood-brain barrier - ABSTRACT The number of older people living with HIV-1 (PLWH) has increased dramatically in the past decade in the US and other Western countries. PLWH experience similar health problems as the general population of older individuals, but at an increased frequency and severity, which is consistent with accentuated aging. Extensive evidence, including studies in the PI’s laboratory, demonstrated amyloid pathology in HIV-1 infection, including dysregulations at the blood-brain barrier (BBB) interface. HIV-infected brains have advanced amyloidopathy, which is characterized by increased amyloid beta (Aβ) deposition mostly in the perivascular space when compared to age-matched controls. Among HIV-associated non-AIDS comorbidities, cerebrovascular diseases, including ischemic stroke, are particularly frequent. While the mechanisms of these conditions are not fully understood, the present application focuses on the role of enhanced procoagulant environment and amyloidopathy as critically important underlying factors. Our current proposal is built on the most exciting and clinically relevant findings resulting from the previous funding cycle, which explored the role of extracellular vesicles (EV) in Aβ transfer to neural progenitor cells (NPCs), and their impaired neurogenesis. We mapped EV cargo proteins and identified Serpine-1 (also known as plasminogen activator inhibitor 1, PAI-1), in various crossroads of neurodegenerative pathways relevant to HIV-associated neurocognitive decline (HAND). This is a paramount discovery because Serpine-1 plays a role in both the generation of a procoagulant environment, and the production and accumulation of Aβ. Therefore, we hypothesize that a procoagulant environment driven by elevated Serpine-1 levels contributes to increased risk of ischemic events, delayed post-ischemic recovery, and enhanced amyloidopathy in HIV-infected brain. Specific mechanisms evaluated in this application include dysregulation of the BBB and enhanced amyloidopathy (Aim 1), reprograming mitochondria and induction of inflammatory responses (Aim 2), and impaired differentiation and migration of NPCs (Aim 3). The complex role of Serpine-1 in HIV-1 infection in the context of both ischemic events and amyloidopathy has been overlooked in the literature, making our proposal conceptually novel. Moreover, this research has potential to generate new therapeutic targets and strategies in aging and HIV-1 infection, especially in prevention and treatment of cerebrovascular comorbidities, including ischemic events.


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 = $540,237 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Mental Health Research Grants	000	17	7/29/2025	NON-COMPETING CONTINUATION	$540,237
														Subtotal = $540,237

Issue Date FY: 2024 ( Subtotal = $540,237 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Mental Health Research Grants	001	16	8/1/2024	NON-COMPETING CONTINUATION	$540,237
2024	2023	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Mental Health Research Grants	000	15	4/30/2024	COMPETING CONTINUATION	$0
2024	2021	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Mental Health Research Grants	002	14	9/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $540,237

Issue Date FY: 2023 ( Subtotal = $541,772 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	000	15	9/19/2023	COMPETING CONTINUATION	$541,772
														Subtotal = $541,772

Issue Date FY: 2021 ( Subtotal = $463,430 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	001	14	4/16/2021	NON-COMPETING CONTINUATION	$463,430
2021	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	000	13	4/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $463,430

Issue Date FY: 2020 ( Subtotal = $608,127 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	001	13	7/2/2020	SUPPLEMENT FOR EXPANSION	$135,455
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	000	13	5/7/2020	NON-COMPETING CONTINUATION	$472,672
														Subtotal = $608,127

Issue Date FY: 2019 ( Subtotal = $481,646 )
2019	2019	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	000	12	4/17/2019	NON-COMPETING CONTINUATION	$481,646
														Subtotal = $481,646

Issue Date FY: 2018 ( Subtotal = $490,356 )
2018	2018	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	000	11	4/23/2018	NON-COMPETING CONTINUATION	$490,356
														Subtotal = $490,356

Issue Date FY: 2017 ( Subtotal = $498,162 )
2017	2017	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	001	10	7/24/2017	COMPETING CONTINUATION	$498,815
2017	2015	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Mental Health Research Grants	000	9	5/2/2017	NON-COMPETING CONTINUATION	-$653
														Subtotal = $498,162

Issue Date FY: 2015 ( Subtotal = $363,375 )
2015	2015	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Mental Health Research Grants	000	9	3/6/2015	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2014 ( Subtotal = $363,375 )
2014	2014	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Mental Health Research Grants	000	8	3/6/2014	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2013 ( Subtotal = $348,840 )
2013	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Mental Health Research Grants	001	7	6/4/2013	NON-COMPETING CONTINUATION	$21,802
2013	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Mental Health Research Grants	000	7	4/3/2013	NON-COMPETING CONTINUATION	$327,038
														Subtotal = $348,840

Issue Date FY: 2012 ( Subtotal = $363,375 )
2012	2012	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Mental Health Research Grants	000	6	2/24/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$363,375
														Subtotal = $363,375

Issue Date FY: 2011 ( Subtotal = $352,688 )
2011	2011	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Mental Health Research Grants	000	5	6/21/2011	COMPETING CONTINUATION	$352,688
														Subtotal = $352,688

Issue Date FY: 2008 ( Subtotal = $277,817 )
2008	2008	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Mental Health Research Grants	000	4	8/11/2008	NON-COMPETING CONTINUATION	$277,817
														Subtotal = $277,817

Issue Date FY: 2007 ( Subtotal = $277,817 )
2007	2007	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Mental Health Research Grants	000	3	8/31/2007	NON-COMPETING CONTINUATION	$277,817
														Subtotal = $277,817

Issue Date FY: 2006 ( Subtotal = $286,115 )
2006	2006	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Mental Health Research Grants	000	2	8/1/2006	NON-COMPETING CONTINUATION	$286,115
														Subtotal = $286,115

Issue Date FY: 2005 ( Subtotal = $292,667 )
2005	2005	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	105 KINKEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Mental Health Research Grants	000	1	9/20/2005	NEW	$292,667
														Subtotal = $292,667

Grand Total All Awards = $7,090,036

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HIV-1 and amyloid beta interactions at the blood-brain barrier

Award Number: R01MH072567

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2005

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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