CD38 activation of TRPM2 in hippocampal neurons contributes to stroke-induced cognitive dysfunction

项目总结 在美国，中风是导致死亡和残疾的主要原因之一。尽管死亡的风险来自 中风随着再灌注治疗的进步而下降，幸存者的数量发展为长期 认知障碍随着患者经历多个认知域的缺陷而增加 包括短期记忆、执行功能和语言。虽然重大的研究工作集中在 大量临床试验表明，在减少缺血性损伤后脑梗塞体积的神经保护策略方面 尽管有效地缩小了梗死体积，但功能结果没有改善。对于这项提议，我认为 神经修复策略的潜在分子靶点，旨在恢复受 缺血性损伤。我专门研究了长期改善Schaffer-CA1海马区的分子靶点 增强(LTP)，被认为是学习和记忆的基础机制之一，在急性和延迟两种情况下 中风后的时间点。通过以海马体通路为靶点，我们的目标是减轻认知负担 许多患者在缺血性卒中后经历的缺陷。 瞬时受体电位相关的2通道(TRPM2)离子通道是一种很有前途的通道 中风后药物干预的候选人。TRPM2是一种非选择性阳离子通道，已被广泛研究 对氧化应激的敏感性及其在各种中枢神经系统病理中的意义。在这里，我们 证明TRPM2整体敲除或药物抑制可恢复海马LTP和- 短暂性大脑中动脉闭塞(MCAO)模型的依赖学习和记忆然而， TRPM2的细胞类型特异性作用及其激活机制在很大程度上仍不清楚。在这项建议中，我 检测TRPM2在小鼠海马区突触和认知损害中的神经元作用 MCAO模型。我还提供了令人信服的初步证据，胞外酶CD38在 大脑中动脉阻塞后的星形胶质细胞，产生激活TRPM2所需的配体，从而产生认知 男性和女性都有缺陷。为了进一步阐明TRPM2的细胞特异性作用及其激活机制，即 建议采用体外和体内电生理学、分子和神经行为方法。在这 提议，我研究了一种新的神经胶质机制来发现急性和慢性疾病的潜在分子靶点。 减轻缺血性卒中后认知功能障碍负担的药物干预。

PROJECT SUMMARY Stroke is one of the leading causes of death and disability in the United States. Though the risk of mortality from stroke has declined with advances in reperfusion therapies, the number of survivors developing long-term cognitive impairment has increased with patients experiencing deficits across multiple cognitive domains including short-term memory, executive function and language. While significant research efforts have focused on neuroprotective strategies to reduce infarct volume following ischemic insult, numerous clinical trials showed no improvements functional outcome, despite effective reduction in infarct volume. For this proposal, I consider potential molecular targets for neurorestorative strategies, which aim to restore neural networks perturbed by ischemic injury. I specifically investigate molecular targets which improve Schaffer-CA1 hippocampal long-term potentiation (LTP), one of the mechanisms thought to underlie learning and memory, at both acute and delayed timepoints following stroke. By targeting hippocampal pathways, we aim to reduce the burden of cognitive deficits experienced by numerous patients following ischemic stroke. The transient receptor potential melastatin-related 2 channel (TRPM2) ion channel serves as a promising candidate for pharmacologic intervention post-stroke. TRPM2 is a nonselective cation channel, well-studied due to its sensitivity to oxidative stress and its implication in various central nervous system pathologies. Here, we demonstrate TRPM2 global knockout or pharmacologic inhibition restores hippocampal LTP and hippocampal- dependent learning and memory in a model of transient middle cerebral artery occlusion (MCAO). However, the cell-type specific role of TRPM2 and its mechanism of activation remain largely unknown. In this proposal, I examine the neuronal contribution of TRPM2 to hippocampal synaptic and cognitive impairment in a mouse model of MCAO. I also provide compelling preliminary evidence the ectoenzyme, CD38, is upregulated in astrocytes following MCAO, generating ligand necessary for TRPM2 activation, thereby producing cognitive deficits in both sexes. To further elucidate the cell-specific role of TRPM2 and its mechanism of activation, I propose to employ in vitro and in vivo electrophysiologic, molecular and neurobehavioral approaches. In this proposal, I investigate a novel neuroglial mechanism to uncover potential molecular targets for acute and chronic pharmacologic intervention to reduce the burden of cognitive disability following ischemic stroke.