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PAR-1 Signaling and HAND

PAR-1 信令和 HAND

基本信息

批准号：
9315952
负责人：
Katherine E Conant
金额：
$ 38.88万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315952
关键词：
Agonist Animal Model Animals Arrestins Behavioral Biochemical Biochemistry Brain Injuries CASP3 gene Cells Cerebral Ischemia Characteristics Clinical Trials Complex Coronary Arteriosclerosis Data DegP protease Depressed mood Disease model Drug Targeting Encephalitis G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Glycogen Synthase Kinases Goals HIV HIV Envelope Protein gp120 HIV-1 Impaired cognition In Vitro Interstitial Collagenase Lead Link Long-Term Depression Magnetic Resonance Spectroscopy Matrix Metalloproteinases Measurable Measures Microglia Morbidity - disease rate Mus Neuronal Injury Neurons Neurotoxins Nitric Oxide Oral PAR-1 Receptor Parkinson Disease Pathology Pathway interactions Phenotype Phosphotransferases Plasmin Protein Dephosphorylation Protein phosphatase Proteinase-Activated Receptors Proteins Research Signal Pathway Signal Transduction Staining method Stains Stimulus Synaptic Transmission Techniques Testing Therapeutic brain tissue experimental study extracellular glycogen synthase kinase 3 beta in vivo inhibitor/antagonist innovation mouse model multi-electrode arrays nervous system disorder neuronal survival neurotoxicity novel novel therapeutics overexpression prevent public health relevance receptor response synaptic function tau Proteins tissue preparation

项目摘要

DESCRIPTION (provided by applicant): 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 ß-arrestins to activate the kinase glycogen synthase kinase-3ß (GSK-3ß) through a novel, non-canonical signaling pathway. Importantly, GSK- 3ß inhibitors have been shown to reduce neuronal injury in response to HAND relevant stimuli. In addition, increased GSK-3ß 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-3ß 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-3ß 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.

描述(申请人提供)：蛋白酶激活受体-1(PAR-1)是一种G蛋白偶联受体(GPCR)，在神经元和小胶质细胞上高表达。包括纤溶酶和基质金属蛋白酶(MMPs)在内的PAR-1激活物的水平在HIV相关性神经疾病(HAND)中显著增加，一项研究表明PAR-1的水平也增加。虽然还没有在手部进行研究，但PAR-1拮抗剂可以在帕金森氏病和脑缺血的动物模型中防止小胶质细胞的激活和神经毒性。最近的研究表明，选定的GPCRs可以通过一种新的、非典型的信号通路与阻滞素结合，激活激酶糖原合成酶激酶-3？(GSK-3？)。重要的是，GSK-3ü抑制剂已被证明可以减少对手部相关刺激的神经元损伤。此外，GSK-3的活性增加与手部相关的病理变化有关，包括小胶质细胞激活、神经毒性和突触传递的长期抑制。在目前的双PI R01方案中，我们假设PAR-1的过度激活刺激了非典型的GPCR依赖的信号通路，从而可测量地促进手部相关的小胶质细胞激活和神经元损伤。我们的计划将是通过体外研究(目标1和2)来测试潜在的机制，以及在体内这一途径对在小鼠模型中观察到的表型变化的相对重要性(目标3)。支持我们假设的初步数据将包括过度表达有效的PAR-1激动剂的小鼠的GSK-3？激活和认知障碍的证据。初步数据还将显示，在从这些动物分离的中枢神经系统来源的细胞中，存在PAR-1依赖的非规范信号。创新来自于对与手相关的相对未被探索的受体的研究，对该受体的新信号通路的研究，以及对独特小鼠模型的使用。创新还来自技术，包括通过多电极阵列记录神经元活动，以及小动物磁共振波谱。我们提案的总体目标是确定辅助疗法的靶点。如果PAR-1的激活可以通过增加GSK-3的活性来刺激与手相关的病理，那么正在开发的更具特异性地抑制该激酶活性的新药可以被考虑用于治疗这种疾病。此外，新开发的口服PAR-1拮抗剂现在正在进行冠状动脉疾病的临床试验，可以考虑用于治疗同样的疾病。