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

项目摘要/摘要 本行政补编申请回应NOT-AG-20-034号《通知 特别兴趣：针对阿尔茨海默氏症的NIH补助金的行政补充 重点关注阿尔茨海默氏症“。在本行政部门的母公司拨款下 补充，R01授权1R01EY031248-01，题为“控制钙的新机制” 治疗和预防早期青光眼神经变性的信号“，我们的目标是 开发新的药物干预控制的新信号通路 青光眼引起的视网膜和视神经神经细胞变性 在美国和世界范围内，视力丧失和失明。具体地说，我们计划确定 作用机制及模型中神经元活性和功能的保存 青光眼系统。家长奖的拟议研究将使我们能够产生 开发补充现有神经保护剂的新神经保护剂所需的临床前数据 针对眼压的治疗。在目前的阿尔茨海默氏症下提出的研究 专注于疾病(AD)的行政补充应用程序将使我们能够在这些新颖的基础上进行改进 临床前数据集，从而开发一种新的治疗策略来保护 AD对中枢神经系统(CNS)神经元的影响。具体地说，我们将测试 假说类似视网膜和视神经的神经元受青光眼的影响，缺乏 AD病理导致中枢神经系统活性和功能降低的细胞防御机制 父母正在开发的新治疗策略可以削弱神经元 获奖。为此，将开发一种新的干预方法，可用于 设计新的治疗方法，可用于受AD影响的中枢神经系统神经元，保护它们 来自氧化应激介导的损伤和功能丧失。三维(3D)生物打印 人类神经细胞结构将被用作AD的体外模型和AD的药物发现 以及采用与父母奖励一致的实验策略的相关痴呆症。这个 拟议的实验将确定有针对性的新治疗策略的潜力 阿尔茨海默病的预防性和神经保护治疗。这一创新战略有可能 为AD提供一流的药物治疗方法。该战略的潜在价值很高 影响在于其预防性和治疗性的能力，以及补充 当前和未来的治疗设计和原理。

PROJECT SUMMARY / ABSTRACT The present administrative supplement application responds to NOT-AG-20-034, “Notice of Special Interest: Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease”. Under the parent grant for the present administrative supplement, R01 grant 1R01EY031248-01, entitled “Novel mechanism controlling calcium signaling to treat and prevent neurodegeneration in early stage glaucoma”, we are targeting a novel signaling pathway for the development of a novel pharmacological intervention to control degeneration of nerve cells in the retina and optic nerve due to glaucoma, a major cause of visual loss and blindness in the United States and worldwide. 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 of the parent award will allow us to generate preclinical data needed for the development of novel neuroprotectants to complement existing therapies targeting intraocular pressure. The research proposed under the present Alzheimer's disease (AD)-focused administrative supplement application will allow us to build on these novel preclinical data sets and thereby to develop a novel therapeutic strategy for the protection of neurons of the central nervous system (CNS) affected by AD. Specifically, we will test the hypothesis that similar to neurons of the retina and optic nerve affected by glaucoma, the lack of cellular defense mechanisms resulting from AD pathology reducing viability and function of CNS neurons can be attenuated by the novel therapeutic strategy under development in the parent award. To this end, a novel intervention approach will be developed that can be exploited to devise novel treatments that can be delivered to CNS neurons affected by AD protecting them from oxidative stress mediated damage and loss of function. Three-dimensional (3D) bio-printed human neural cell constructs will be used as in vitro models for AD and for drug discovery in AD and related dementias employing experimental strategies aligned with the parent award. The proposed experiments will determine the potential of the targeted novel therapeutic strategy for preventative and neuroprotective therapies in AD. The innovative strategy has the potential to generate a first-in-class pharmacotherapy approach for AD. The strategy's potentially high impact lies in its capacity to be both preventative and therapeutic in nature and to complement current and future treatment designs and rationales.