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Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment

Award Number: R01MH115786
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV- associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. One of the explanations could be constant compromise of blood brain barrier (BBB) driven by chronic inflammatory responses documented in HIV-infected individuals even with well-controlled virus replication yet with HAND progression. Chronic neuroimmune activation is present in ART-treated patients as indicated by elevated levels of soluble inflammatory factors in the cerebrospinal fluid and blood. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. BBB dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury has been documented in animal models of diabetes showing memory deficits and was associated with dysfunction of brain pericytes supporting endothelial cells. Taking together clinical and experimental data, BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. We propose that cognitive impairment in HIV- infected individuals is mediated by BBB injury that is further aggravated by metabolic alterations associated with DM causing HAND. Preliminary data support this idea showing elevated glucose levels correlated with increased BBB permeability, cognitive impairment, microglia activation and loss of pericytes in animal models for DM types 1 and 2. We found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules after exposure to HIV and DM-relevant stimuli. We hypothesize that prevention of BBB compromise in DM/HIV will diminish neurocognitive decline independently of tight glucose control. We will identify biomarkers of such BBB injury, correlate with barrier damage and cognitive decline, define signaling pathways associated with BBB injury in DM/HIV and test novel treatment approaches. We will study the contribution of DM- and HIV- mimicking conditions on cognition and BBB injury in cross-validating experiments using well- established in vitro systems (co-culture of human primary brain microvascular endothelial cells/primary human brain pericytes), functional assays, animal models of DM types 1 and 2 combined with HIV brain exposure and `humanized' NSG mice with chronic HIV infection and diabetes. Results of such studies will open opportunities for very much needed individualized treatment for HAND.


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: 2022 ( Subtotal = $502,493 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	5	4/21/2022	NON-COMPETING CONTINUATION	$502,493
														Subtotal = $502,493

Issue Date FY: 2021 ( Subtotal = $508,199 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	4	5/3/2021	NON-COMPETING CONTINUATION	$508,199
														Subtotal = $508,199

Issue Date FY: 2020 ( Subtotal = $525,220 )
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	3	5/7/2020	NON-COMPETING CONTINUATION	$525,220
														Subtotal = $525,220

Issue Date FY: 2019 ( Subtotal = $538,058 )
2019	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	2	4/18/2019	NON-COMPETING CONTINUATION	$538,058
														Subtotal = $538,058

Issue Date FY: 2018 ( Subtotal = $455,369 )
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	1	6/11/2018	NEW	$455,369
														Subtotal = $455,369

Grand Total All Awards = $2,529,339

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Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment

Award Number: R01MH115786

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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