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（由申请人提供）：中风是美国的第三大死亡原因，也是长期残疾的主要原因。不幸的是，很少有可用的药物治疗能够限制中风后损害。因此，迫切需要进行卒中后疗法的新颖目标。我们最近确定了分泌的prosaposin及其活性碎片prosaptide是脑表达的G蛋白偶联受体GPR37和GPR37L1的配体。有趣的是，作为一种肽，已对Prosaptide进行了二十年的广泛研究，可改善中风模型的恢复。但是，目前尚不清楚Prosaptide是否通过刺激GPR37和/或GPR37L1在体内发挥这些保护作用。此外，对于GPR37和GPR37L1下游的信号传导途径可能与Prosaposin和Prosaptide的保护作用有关。在该项目中，我们将研究Prosaptide对原发性皮质星形胶质细胞的保护作用，这是一种表达GPR37和GPR37L1的细胞类型，并阐明了这些受体下游的信号传导途径，介导了氧气/GLUC折纸后prosaptide治疗的促硫化物效应。我们还将寻求了解GPR37＆GPR37L1下游的保护性信号通路的机制，因为目前对此主题尚无任何了解。此外，我们将在体内进行平行研究，在该研究中，我们将研究野生型小鼠局灶性脑缺血引起的损害，以及缺乏GPR37和/或GPR37L1表达的小鼠，以评估这些受体及其下游信号传导在减轻疾病中的损害的重要性。这些研究将提供有关GPR37＆GPR37L1作为中风治疗的新目标的潜在实用性的见解，并阐明了这些受体下游的信号传导途径与它们的保护作用相关。