Novel mechanism controlling calcium signaling to treat and prevent neurodegeneration in early stage glaucoma

项目摘要/摘要 这项建议是对NEI的战略计划的回应，NEI最近在《愿景研究： 需求、差距和机会“，并重点介绍了我们对一种新型神经元的最新发现 起源于衰老的机制和眼病的生物机制已确定 作为一项高度的规划优先事项。这项研究的目标是一种新的神经保护机制。 利用细胞内钙通道作为药物靶点治疗青光眼神经变性。 具体地说，我们计划确定作用机制，并测量神经元的保存。 青光眼模型系统的生存能力和功能。拟议的研究将使我们能够产生 开发新的神经保护剂补充现有治疗所需的临床前数据 靶向眼压：视网膜神经节细胞内游离钙离子浓度 中枢神经系统的其他神经元受到高度调控，在衰老过程中容易受到失调的影响。对于 急性和慢性退行性疾病的发展，包括青光眼，降低生存能力和 视网膜神经节细胞(RGCs)的功能多项研究表明，细胞内秒的变化 信使浓度和病理性细胞内钙离子浓度升高促进 发病机制。目前的应用将检验视网膜神经节细胞的钙信号在功能上的假设 受神经退行性损伤后视网膜神经节细胞上调的即刻早期基因产物调控 产生一种细胞防御机制。这一假设建立在强有力的初步证据基础上 视网膜的正常老化在机制上类似于青光眼疾病的过程，可以加以利用 设计治疗青光眼的新方法。为检验这一假设而设计的拟议实验将 研究这种相互作用背后的分子、细胞和功能机制 实验诱导的青光眼模型的疾病状态。建议的总体目标是 研究旨在确定一种新的RGC神经保护机制，并确定其作为策略的潜力 用于针对视网膜节细胞的神经保护疗法。这种治疗方法将有可能既是 预防和治疗的性质，并补充现有的治疗设计和理由。

Project Summary/Abstract The proposal is in response to NEI's strategic plan, described recently by NEI in “Vision Research: Needs, Gaps, and Opportunities”, and focuses on our most recent discoveries of a novel neuronal mechanism rooted at the intersection of aging and the biological mechanisms of eye disease identified as a high programmatic priority. The proposed research targets a novel mechanism of neuroprotection utilizing intracellular calcium channels as drug targets to treat neurodegeneration in glaucoma. Specifically, we plan to determine mechanisms of action and to measure preservation of neuronal viability and function in model systems of glaucoma. The proposed research will allow us to generate preclinical data needed for the development of novel neuroprotectants to complement existing therapies targeting intraocular pressure: The intracellular free Ca2+ concentration of retinal ganglion cells like in other neurons of the CNS is highly regulated and subject to dysregulation during aging. For the development of acute and chronic degenerative diseases including glaucoma reducing the viability and function of retinal ganglion cells (RGCs) several studies indicate that both changes in intracellular second messenger concentration and pathological increases in the intracellular Ca2+ concentration promote pathogenesis. The present application will test the hypothesis that Ca2+ signaling of RGCs is functionally regulated by an immediate early gene product upregulated in RGCs after a neurodegenerative insult to generate a cellular defense mechanism. This hypothesis is based on strong preliminary evidence that normal aging of the retina is mechanistically similar to glaucoma disease processes and can be exploited to devise novel treatments for glaucoma. The proposed experiments designed to test this hypothesis will investigate the molecular, cellular and functional mechanisms underlying this interaction under experimentally induced disease conditions in models of glaucoma. The overall goal of the proposed study is to identify a novel mechanism of RGC neuroprotection and determine its potential as a strategy for neuroprotective therapies targeting RGCs. This therapy approach will have the potential to be both preventative and therapeutic in nature and to complement existing treatment designs and rationales.