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

项目摘要 中风是美国死亡和残疾的主要原因之一。虽然死亡的风险， 随着再灌注治疗的进步，中风的幸存者人数已经下降， 随着患者经历多个认知领域的缺陷， 包括短期记忆执行功能和语言虽然大量的研究工作集中在 许多临床试验表明， 尽管梗死体积有效减小，但功能结局无改善。对于这一建议，我认为 神经恢复策略的潜在分子靶点，旨在恢复受干扰的神经网络。 缺血性损伤我专门研究了改善Schaffer-CA 1海马长期 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 卒中后的时间点。通过靶向海马通路，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功能缺陷。 瞬时受体电位melastatin相关2通道（TRPM 2）离子通道作为一种有前途的 中风后药物干预的候选人。TRPM 2是一种非选择性阳离子通道，由于其具有良好的生物学特性， 其对氧化应激的敏感性及其在各种中枢神经系统病理学中的意义。这里我们 证明TRPM 2整体敲除或药理学抑制恢复海马LTP和海马- 短暂性大脑中动脉闭塞（MCAO）模型中的依赖性学习和记忆。但 TRPM 2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。在这份提案中，我 检查TRPM 2对小鼠海马突触和认知损伤的神经元贡献 MCAO模型我还提供了令人信服的初步证据，胞外酶，CD 38，是上调， 星形胶质细胞在MCAO后，产生TRPM 2激活所必需的配体，从而产生认知功能。 两种性别都有缺陷。为了进一步阐明TRPM 2的细胞特异性作用及其激活机制，我 建议采用体外和体内电生理学、分子和神经行为方法。在这 我的建议，我调查了一种新的神经胶质细胞机制，以发现潜在的分子靶点，急性和慢性 药物干预以减轻缺血性卒中后认知障碍的负担。

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.