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

项目总结/摘要 该提案是对NEI战略计划的回应，NEI最近在“愿景研究： 需要，差距和机会”，并侧重于我们最近发现的一种新的神经元 机制植根于衰老和眼科疾病的生物学机制的交叉点确定 作为一个高度优先的项目。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中的神经变性。 具体来说，我们计划确定作用机制，并衡量神经元的保护， 青光眼模型系统的生存力和功能。这项研究将使我们能够产生 开发新的神经保护剂以补充现有疗法所需的临床前数据 靶向眼内压：视网膜神经节细胞内游离Ca 2+浓度， CNS的其它神经元在老化过程中受到高度调节并发生调节异常。为 急性和慢性退行性疾病的发展，包括青光眼，降低了生存能力， 视网膜神经节细胞（RGC）的功能几项研究表明，细胞内第二次细胞周期的变化， 信使浓度和细胞内Ca 2+浓度的病理性增加促进了 发病机制本申请将测试RGCs的Ca 2+信号传导在功能上与RGCs的Ca 2+信号传导相关的假设。 在神经退行性损伤后，由RGC中上调的立即早期基因产物调节， 产生细胞防御机制这一假设是基于强有力的初步证据， 视网膜的正常衰老在机制上与青光眼疾病过程相似，可以利用 来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 研究这种相互作用的分子，细胞和功能机制， 在青光眼模型中实验诱导的疾病状况。拟议的总体目标 研究旨在确定RGC神经保护的新机制，并确定其作为策略的潜力 用于针对RGC的神经保护疗法。这种治疗方法将有可能成为两个 预防和治疗性质，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.