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

控制钙信号传导以治疗和预防早期青光眼神经变性的新机制

• 批准号: 10288383
• 负责人: Peter Koulen
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288383
• 关键词: 3-Dimensional; Administrative Supplement; Affect; Aftercare; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Apoptosis; Attenuated; Award; Basic Science; Biological Models; Biological Products; Biomedical Engineering; Biomimetics; Blindness; Brain; Calcium; Calcium Channel; Calcium Signaling; Cell membrane; Cells; Characteristics; Chronic; Clinical Research; Cognitive; Complement; Data; Data Set; Defense Mechanisms; Dementia; Development; Drug Design; Drug Modelings; Drug Targeting; Future; Glaucoma; Goals; Grant; Health; Healthcare; Homeostasis; Homer 1; Homer 1a; Homer protein; Human; Immediate-Early Genes; Intervention; Knowledge; Measures; Mediating; Memory; Methods; Minority; Nature; Nerve Degeneration; Neuraxis; Neurons; Neuroprotective Agents; Optic Nerve; Oxidative Stress; Parents; Pathology; Pathway interactions; Performance; Pharmacology; Pharmacotherapy; Physiologic Intraocular Pressure; Physiological; Population; Pre-Clinical Model; Prevention; Prevention strategy; Protein Isoforms; Proteins; Publishing; Receptor Signaling; Research; Retina; Retinal Ganglion Cells; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Synaptic Transmission; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Translational Research; United States; United States National Institutes of Health; Visual impairment; base; brain tissue; clinical translation; clinically relevant; design; drug development; drug discovery; epidemiology study; experimental study; functional improvement; gene product; health care delivery; health disparity; improved; in vitro Model; innovation; insight; interest; loss of function; neuroprotection; new therapeutic target; novel; novel therapeutic intervention; parent grant; pre-clinical; preservation; prevent; retinal neuron; targeted treatment; tau Proteins; therapeutic target; therapy design; treatment strategy

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.

项目总结/摘要 本行政补充申请响应NOT-AG-20-034，“通知 特别兴趣：以阿尔茨海默氏症为重点的NIH赠款的行政补充， 专注于老年痴呆症”。根据本行政年度的父母补助金， 增刊，R 01授权1 R 01 EY 031248 -01，标题为“控制钙的新机制 治疗和预防早期青光眼神经退行性变的信号”，我们针对 新的信号传导途径，用于开发新的药理学干预， 由于青光眼引起的视网膜和视神经中的神经细胞变性， 视力丧失和失明在美国和世界各地。具体来说，我们计划确定 作用机制，并测量模型中神经元活力和功能的保留 系统的青光眼。父母奖的拟议研究将使我们能够产生 开发新型神经保护剂以补充现有的神经保护剂所需的临床前数据 针对眼内压的治疗。这项研究是根据目前的阿尔茨海默氏症提出的 疾病（AD）为重点的行政补充申请将使我们能够建立在这些新的 临床前数据集，从而开发一种新的治疗策略， 受AD影响的中枢神经系统（CNS）的神经元。具体来说，我们将测试 假设类似于视网膜和视神经受青光眼影响的神经元， AD病理导致的细胞防御机制降低CNS的活力和功能 神经元可以通过在母体中开发的新的治疗策略来减弱 奖为此，将开发一种新的干预方法， 设计新的治疗方法，可以传递到受AD影响的CNS神经元，保护它们 氧化应激介导的损伤和功能丧失。三维（3D）生物打印 人神经细胞构建体将用作AD的体外模型和AD的药物发现 以及相关痴呆症患者采用与父母奖励一致的实验策略。的 拟议的实验将确定有针对性的新的治疗策略的潜力， 预防和神经保护治疗。创新战略有可能 为AD提供一流的药物治疗方法。这个策略的潜在风险很高 其影响在于其具有预防和治疗性质的能力， 当前和未来的治疗设计和原理。