Protease activated receptor-1 (PAR-1) is a G protein coupled receptor (GPCR) that is highly expressed on neurons and microglia. Levels of PAR-1 activators, including plasmin and matrix metalloproteinases (MMPs), are substantially increased in HIV associated neurological disorders (HAND) and one study has shown that levels of PAR-1 are increased as well. Though not yet studied in the context of HAND, PAR-1 antagonists can prevent microglial activation and neurotoxicity in animal models of Parkinson's disease and cerebral ischemia. Recent studies have shown that select GPCRs can associate with ?-arrestins to activate the kinase glycogen synthase kinase-3??(GSK-3?) through a novel, non-canonical signaling pathway. Importantly, GSK- 3?? inhibitors have been shown to reduce neuronal injury in response to HAND relevant stimuli. In addition, increased GSK-3?? activity has been implicated in HAND relevant pathology including microglial activation, neurotoxicity, and long term depression of synaptic transmission. In the present dual PI R01 proposal, we hypothesize that excess activation of PAR-1 stimulates non- canonical GPCR dependent signaling pathways to measurably contribute to HAND relevant microglial activation and neuronal injury. Our plan will be to test underlying mechanisms with in vitro studies (Aims 1 and 2) and the relative in vivo importance of this pathway to phenotypic changes observed in mouse models (Aim 3). Preliminary data in support of our hypothesis will include evidence for GSK-3?? activation and cognitive impairment in mice that overexpress a potent PAR-1 agonist. Preliminary data will also show evidence for PAR-1 dependent, non-canonical signaling, in CNS derived cells isolated from these animals. Innovation comes from the study of a relatively unexplored receptor as related to HAND, the study of a novel signaling pathway for this receptor, and the use of a unique mouse model. Innovation also comes from techniques that include recordings of neuronal activity via multielectrode arrays, and small animal magnetic resonance spectroscopy. The overall goal of our proposal is to identify targets for adjunct therapeutics. If PAR-1 activation can stimulate HAND relevant pathology through increased GSK-3?? activity, novel drugs being developed to more specifically inhibit the activity of this kinase could be considered for treatment of this condition. Moreover, newly developed orally available PAR-1 antagonists that are now in clinical trials for coronary artery disease might be considered for treatment of the same.
HIV associated neurological disorders cause significant morbidity and at present, therapeutics to reduce associated brain inflammation are limited. Research into whether drugs that target protease activated receptors is warranted. Antagonists for these receptors reduce brain injury in other disease models.
|Jiang, Huiyi; Liu, Shicheng; Geng, Xinling et al. (2018) Pacing Hippocampal Sharp-Wave Ripples With Weak Electric Stimulation. Front Neurosci 12:164|
|Sun, Zhi Yong; Bozzelli, P Lorenzo; Caccavano, Adam et al. (2018) Disruption of perineuronal nets increases the frequency of sharp wave ripple events. Hippocampus 28:42-52|
|Li, Yan; Chen, Xin; Dzakpasu, Rhonda et al. (2017) Dopamine-dependent effects on basal and glutamate stimulated network dynamics in cultured hippocampal neurons. J Neurochem 140:550-560|
|Winland, Carissa D; Welsh, Nora; Sepulveda-Rodriguez, Alberto et al. (2017) Inflammation alters AMPA-stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons. Eur J Neurosci 46:2519-2533|
|Conant, Katherine; Daniele, Stefano; Bozzelli, P Lorenzo et al. (2017) Matrix metalloproteinase activity stimulates N-cadherin shedding and the soluble N-cadherin ectodomain promotes classical microglial activation. J Neuroinflammation 14:56|
|Li, Yan; Partridge, John; Berger, Carissa et al. (2016) Dopamine increases NMDA-stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase-dependent mechanism. Eur J Neurosci 43:194-203|
|Allen, Megan; Ghosh, Suhasini; Ahern, Gerard P et al. (2016) Protease induced plasticity: matrix metalloproteinase-1 promotes neurostructural changes through activation of protease activated receptor 1. Sci Rep 6:35497|
|Valente, Maria Maddalena; Allen, Megan; Bortolotto, Valeria et al. (2015) The MMP-1/PAR-1 Axis Enhances Proliferation and Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells. Neural Plast 2015:646595|
|Conant, Katherine; Allen, Megan; Lim, Seung T (2015) Activity dependent CAM cleavage and neurotransmission. Front Cell Neurosci 9:305|