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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZMH1-ERB-X)
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Children's Hospital of Philadelphia
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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
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
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
Spitsin, Sergei; Tuluc, Florin; Meshki, John et al. (2013) Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. Neuroimmunomodulation 20:247-55
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
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