GPR37 & GPR37L1 signaling pathways promoting cell survival: relevance to stroke

探地雷达37

• 批准号: 9117648
• 负责人: Randy A. Hall
• 金额: $ 34.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117648
• 关键词: Agonist; Arrestins; Astrocytes; Brain; Cause of Death; Cell Death; Cell Survival; Cell model; Cells; Cerebral Ischemia; Coupling; Cultured Cells; Development; Future; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GPR37 receptor; GTP-Binding Proteins; Glucose; Health; In Vitro; Infarction; Knockout Mice; Knowledge; Ligands; Light; Literature; Mediating; Mus; Nervous System Trauma; Oxygen; Pathway interactions; Peptides; Pharmacotherapy; Physiological; Prevention; Property; Proteins; RIPK1 gene; Recovery; Regulation; Reporting; Rodent Model; Role; Signal Pathway; Signal Transduction; Staging; Stream; Stroke; Therapeutic; Ubiquitination; Wild Type Mouse; Work; cell type; deprivation; disability; drug discovery; functional disability; improved; in vivo; inhibitor/antagonist; insight; knock-down; mouse model; novel; positive allosteric modulator; post stroke; prosaptide; protective effect; receptor; receptor coupling; scaffold; small molecule; stroke therapy; stroke treatment; therapeutic target

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the USA and the leading cause of long- term disability. Unfortunately, there are few available pharmacotherapies capable of limiting damage following a stroke. For this reason, novel targets for post-stroke therapies are desperately needed. We recently identified the secreted factor prosaposin and its active fragment prosaptide as ligands for the brain-expressed G protein-coupled receptors GPR37 and GPR37L1. Interestingly, prosaptide has been extensively studied for two decades as a peptide that improves recovery in rodent models of stroke. However, it is not known at present if prosaptide exerts these protective effects in vivo via stimulation of GPR37 and/or GPR37L1. Moreover, nothing is known about the signaling pathways downstream of GPR37 and GPR37L1 that might be relevant to the protective actions of prosaposin and prosaptide. In this project, we will study the protective actions of prosaptide on primary cortical astrocytes, a cell type that expresses both GPR37 & GPR37L1, and elucidate the signaling pathways downstream of these receptors that mediate the pro-survival effects of prosaptide treatment following oxygen/glucose deprivation. We will also seek to understand the mechanisms by which the protective signaling pathways downstream of GPR37 & GPR37L1 are regulated, since nothing is currently known about this topic. Furthermore, we will perform parallel studies in vivo in which we will study damage induced by focal cerebral ischemia in wild- type mice as well as mice lacking expression of GPR37 and/or GPR37L1 in order to assess the importance of these receptors and their downstream signaling pathways in mitigating damage following a stroke and mediating the protective actions of prosaptide. These studies will provide insights into the potential utility of GPR37 & GPR37L1 as novel targets for the treatment of stroke and also shed light on the signaling pathways downstream of these receptors that are relevant to their protective effects.

描述(申请人提供)：中风是美国第三大致死原因，也是导致长期残疾的首要原因。不幸的是，几乎没有可用的药物疗法能够限制中风后的损害。出于这个原因，人们迫切需要中风后治疗的新靶点。我们最近发现，分泌因子丙皂苷及其活性片段是脑表达的G蛋白偶联受体GPR37和GPR37L1的配基。有趣的是，20年来，人们一直在广泛研究普罗萨德，作为一种促进中风啮齿动物模型恢复的多肽。然而，目前尚不清楚普罗沙普在体内是否通过刺激GPR37和/或GPR37L1发挥这些保护作用。此外，GPR37和GPR37L1下游的信号通路可能与丙皂苷和丙皂肽的保护作用有关，目前还不清楚。在这项研究中，我们将研究普罗萨肽对原代皮质星形胶质细胞的保护作用，这是一种同时表达GPR37和GPR37L1的细胞类型，并阐明这些受体下游的信号通路，这些信号通路介导普罗萨肽治疗缺氧/葡萄糖剥夺后的促生存效应。我们还将试图了解GPR37和GPR37L1下游的保护性信号通路受到调控的机制，因为目前对这一主题一无所知。此外，我们将在体内进行平行研究，研究野生型小鼠以及GPR37和/或GPR37L1表达缺失的小鼠的局灶性脑缺血造成的损伤，以评估这些受体及其下游信号通路在减轻中风后损伤和介导丙皂肽的保护作用中的重要性。这些研究将为GPR37和GPR37L1作为治疗中风的新靶点的潜在用途提供见解，并阐明这些受体下游与其保护作用相关的信号通路。