The goals of this project are to determine the role of neurokinin-1 receptor (NKIR) in the interactions between HIV receptors and inhibitory drugs that target elements of the NKIR pathway to block or reduce HIV infectivity in activated monocytes (MC) and monocyte-derived macrophages (MDM) and to analyze the role of NKIR-mediated signaling and the effects of antagonists on HIV-1 infection in brain cells, specifically astrocytes and neural progenitor cells. 1) We will characterize NKIR expression in activated monocyte/macrophages and determine whether differential isoform expression affects interactions between NK1R, the HIV co-receptor CCR5, and HIV infectivity. We will study NKI R expression in activated monocyte and macrophages as well as cellular interactions between the CCR5 and NKIR. [...] 4) NKIR expression in human multipotential neural progenitor cells and their response to SP-induced NKIR activation and the effect of HIV gp120 will be characterized. We will determine the effects of SP and gp120 on human NPC phenotype, NKIR expression, and response to CXCL12/SDF-1 as measured by assays of proliferation and chemotaxis. The effect of the NKIR antagonist aprepitant on neural progenitor phenotype and responsiveness to CXCL12/SDF-1 under conditions of SP-induced NKIR activation and in the presence of HIV gp120 will be evaluated.

Public Health Relevance

In order to determine the potential therapeutic use of NKIR antagonists as anti-HIV adjunct therapy it is essential to understand the cellular mechanisms involved. Macrophages, astroglia and neural progenitor cells are the main cells involved in neuron-AlDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH090325-05
Application #
8526562
Study Section
Special Emphasis Panel (ZMH1-ERB-X)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$155,684
Indirect Cost
$61,043
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Barrett, Jeffrey S; Spitsin, Sergei; Moorthy, Ganesh et al. (2016) Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. J Transl Med 14:148
Douglas, Steven D (2016) Substance P and sickle cell disease-a marker for pain and novel therapeutic approaches. Br J Haematol 175:187-188
McGuire, Jennifer L; Gill, Alexander J; Douglas, Steven D et al. (2015) Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neurovirol 21:439-48
Tebas, Pablo; Spitsin, Sergei; Barrett, Jeffrey S et al. (2015) Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults. AIDS 29:931-9
McGuire, Jennifer L; Kempen, John H; Localio, Russell et al. (2015) Immune markers predictive of neuropsychiatric symptoms in HIV-infected youth. Clin Vaccine Immunol 22:27-36
Tuluc, Florin; Meshki, John; Spitsin, Sergei et al. (2014) HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J Leukoc Biol 96:143-50
McGuire, Jennifer L; Barrett, Jeffrey S; Vezina, Heather E et al. (2014) Adjuvant therapies for HIV-associated neurocognitive disorders. Ann Clin Transl Neurol 1:938-52
Barrett, Jeffrey S; Bajaj, Gaurav; McGuire, Jennifer et al. (2014) Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant. Curr HIV Res 12:121-31
Barrett, Jeffrey S; McGuire, Jennifer; Vezina, Heather et al. (2013) PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions? J Clin Psychopharmacol 33:725-8
Schwartz, Lynnae; Spitsin, Sergei V; Meshki, John et al. (2013) Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor. J Neurovirol 19:219-27

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