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

描述（由申请人提供）：中风是美国第三大死亡原因，也是导致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的损害。因此，迫切需要中风后治疗的新靶点。我们最近发现分泌因子prosaposin及其活性片段prosaptide是脑表达的G蛋白偶联受体GPR37和GPR37L1的配体。有趣的是，二十年来，prosaptide作为一种肽被广泛研究，可以改善啮齿动物中风模型的恢复。然而，目前尚不清楚prosap肽是否通过刺激GPR37和/或GPR37L1在体内发挥这些保护作用。此外，GPR37和GPR37L1的下游信号通路可能与prosaposin和prosaptide的保护作用有关，目前尚不清楚。在本项目中，我们将研究prosap肽对原代皮质星形胶质细胞（一种同时表达GPR37和GPR37L1的细胞类型）的保护作用，并阐明这些受体下游的信号通路，这些信号通路介导prosap肽治疗在缺氧/葡萄糖剥夺后的促生存作用。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，我们将研究野生型小鼠以及缺乏GPR37和/或GPR37L1表达的小鼠局灶性脑缺血引起的损伤，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prosap肽保护作用中的重要性。这些研究将深入了解GPR37和GPR37L1作为中风治疗新靶点的潜在效用，并揭示这些受体下游与其保护作用相关的信号通路。

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.