PAR-1 Signaling and HAND

PAR-1 信令和 HAND

基本信息

批准号：
8739684
负责人：
Katherine E Conant
金额：
$ 38.49万
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/8739684
关键词：
Agonist Animal Model Animals Arrestins Behavioral Biochemical Biochemistry Brain Injuries Cells Cerebral Ischemia Characteristics Clinical Trials Complex Coronary Arteriosclerosis Data Depressed mood Disease model Drug Targeting Encephalitis G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals HIV HIV Envelope Protein gp120 HIV-1 Impaired cognition In Vitro Interstitial Collagenase Lead Ligands Link Long-Term Depression Magnetic Resonance Spectroscopy Matrix Metalloproteinases Measures Microglia Morbidity - disease rate Mus N-terminal Neuronal Injury Neurons Neurotoxins Nitric Oxide PAR-1 Receptor Parkinson Disease Pathology Pathway interactions Peptide Hydrolases Peptides Pharmaceutical Preparations Phenotype Phosphotransferases Plasmin Protein Dephosphorylation Protein phosphatase Proteinase-Activated Receptors Proteins Relative (related person)Research Signal Pathway Signal Transduction Staining method Stains Stimulus Synaptic Transmission Techniques Testing Therapeutic brain tissue caspase-3 extracellular in vivo inhibitor/antagonist innovation mouse model nervous system disorder neuronal survival neurotoxicity novel overexpression prevent public health relevance receptor research study 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 ?-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.

描述（由申请人提供）：蛋白酶活化的受体1（PAR-1）是G蛋白偶联受体（GPCR），在神经元和小胶质细胞上高度表达。包括纤溶酶和基质金属蛋白酶（MMP）在内的PAR-1激活剂水平在HIV相关的神经系统疾病（手）中显着升高，一项研究表明，PAR-1的水平也增加了。尽管尚未在手背景下进行研究，但PAR-1拮抗剂可以预防帕金森氏病和脑缺血动物模型中的小胶质细胞激活和神经毒性。最近的研究表明，精选的GPCR可以与 - arrestin相关联，以激活激酶糖原合酶激酶-3 ??（GSK-3？）通过一种新型的非典型信号传导途径。重要的是，GSK-3？已显示抑制剂可减少与手相关刺激的响应。另外，GSK-3增加了？活性与手相关病理有关，包括小胶质细胞激活，神经毒性和长期突触传播的抑郁症。在目前的双PI R01提案中，我们假设PAR-1的过量激活刺激了非规范GPCR依赖性信号传导途径，从而可衡量地有助于手工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）测试基本机制，并且这种途径在小鼠模型中观察到的表型变化的相对重要性（AIM 3）。支持我们假设的初步数据将包括GSK-3的证据？过表达有效的PAR-1激动剂的小鼠的激活和认知障碍。初步数据还将显示从这些动物分离的CNS衍生细胞中的PAR-1依赖性，非传统信号传导的证据。创新来自与手相关的相对未开发的受体，该受体的新信号通路的研究以及使用独特的小鼠模型的研究。创新还来自包括通过多电极阵列记录神经元活动的技术，以及小动物磁共振光谱。我们建议的总体目标是确定辅助治疗剂的目标。如果PAR-1激活可以通过增加的GSK-3刺激相关病理？活性，开发出来更具体地抑制这种激酶的活性的新型药物可以考虑用于治疗这种情况。此外，在冠状动脉疾病临床试验中，新开发的口服PAR-1拮抗剂可能被考虑用于治疗。