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Targeting monocyte/macrophage cathepsin B interactome in HIV-1 neurocognitive disorders

Award Number: SC1GM113691
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2021

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Targeting monocyte/macrophage cathepsin B interactome in HIV-1 neurocognitive disorders - Targeting monocyte/macrophage cathepsin B interactome in HIV-1 neurocognitive disorders ABSTRACT Chronic human immunodeficiency virus type one (HIV-1) infection leads to a spectrum of neurological and cognitive abnormalities, known collectively as HIV-associated neurocognitive disorders (HAND). HAND remains prevalent, particularly in its milder forms, despite effective combination antiretroviral therapy (cART). The pathogenesis of HAND is involves HIV-infected perivascular macrophages and microglia, whose activation leads to the release of pro-inflammatory cytokines and other soluble factors toxic to neurons. One factor that may be involved in macrophage-mediated HIV neurotoxicity is cathepsin B, a cysteine protease. We recently demonstrated that monocyte-derived macrophages (MDM) secreted, cathepsin B has increased neurotoxic activity in vitro. In studies of our Hispanic women cohort, we observed increased expression of both cathepsin B and cystatin B in monocytes of women with HAD on cART with no comorbid conditions. Studies are needed to determine the role of monocyte cathepsin B, cystatins B and C, as potential biomarkers for HAND by flow cytometry. A pilot study of limited samples post-mortem brain tissue indicated that cathepsin B is also upregulated in the CNS of patients with HAND [1]. New preliminary studies of MDM secreted interactome demonstrate that cathepsin B interacts with MMP-9 in uninfected cells but this interaction disappears in HIV infection and develops a new interaction with serum amyloid P component (SAPC), related to amyloid deposition in Alzheimer's disease (AD). Studies in the literature also suggest that cathepsin B might be involved in amyloid-beta (Aß)- related inflammatory response, which results in neuronal death. This new role of cathepsin B in HIV infection deserves further studies. Our long-term goal is to determine the potential of the cathepsin B system as a diagnostic tool and therapeutic target for HAND and the mechanisms whereby cathepsin B dysregulation causes neuronal cell dysfunction and death. Our central hypothesis is that increased secretion of monocyte-derived cathepsin B after HIV infection causes neuronal dysfunction and death, and contributes to the pathogenesis of HAND. The proposed research is conceptually innovative because the role of the cathepsin B as a potential early blood biomarker of HAND has not been explored. Understanding how dysregulation of the cathepsin B interacting proteins in the HIV-infected MDM secretome contributes to neurotoxicity using primary human neurons could elucidate novel targets for therapy. The specific aims are: 1) Create a longitudinal expression profile of cathepsin B and cystatins B and C in CD14+ monocytes from HAND patients. 2) Characterize of the interactome of MDM-secreted cathepsin B and its involvement in HIV-induced neuronal death; 3) Determine the translational significance of cathepsin B interactome in human post-mortem brain tissue. The proposed studies will significantly advance the HIV field by providing new clinical diagnostic tools, new pathways, and possible complementary therapies against 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: 2021 ( Subtotal = -$37,790 )
2021	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	4	8/28/2021	SUPPLEMENT FOR EXPANSION	-$26,273
2021	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	4	5/5/2021	NON-COMPETING CONTINUATION	-$11,517
														Subtotal = -$37,790

Issue Date FY: 2019 ( Subtotal = $367,062 )
2019	2019	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	4	4/29/2019	SUPPLEMENT FOR EXPANSION	$367,062
2019	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	4	4/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $367,062

Issue Date FY: 2018 ( Subtotal = $375,000 )
2018	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	4	2/6/2018	NON-COMPETING CONTINUATION	$337,500
2018	2018	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	4	5/11/2018	NON-COMPETING CONTINUATION	$37,500
														Subtotal = $375,000

Issue Date FY: 2017 ( Subtotal = $375,000 )
2017	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	000	3	1/11/2017	NON-COMPETING CONTINUATION	$337,500
2017	2017	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Biomedical Research and Research Training	001	3	7/12/2017	NON-COMPETING CONTINUATION	$37,500
														Subtotal = $375,000

Issue Date FY: 2016 ( Subtotal = $375,000 )
2016	2016	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	2	1/29/2016	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2015 ( Subtotal = $375,000 )
2015	2015	UNIVERSITY OF PUERTO RICO - MEDICAL SCIENCE CAMPUS	POST OFFICE BOX 365067	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	1	4/17/2015	NEW	$375,000
														Subtotal = $375,000

Grand Total All Awards = $1,829,272

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Targeting monocyte/macrophage cathepsin B interactome in HIV-1 neurocognitive disorders

Award Number: SC1GM113691

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2021

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