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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目摘要 /摘要当前的行政补充申请响应对非AG-20-034的响应，“通知特殊兴趣：阿尔茨海默氏症专注于NIH赠款的行政补品专注于阿尔茨海默氏病。” 补充，R01授予1R01EY031248-01，标题为“控制钙的新机制信号传导以治疗和预防早期青光眼的神经退行性””，我们针对A 用于开发新的药理学干预措施的新型信号通路因青光眼引起的视网膜和视神经的神经细胞的变性，这是主要原因美国和全球的视觉丧失和失明。具体来说，我们计划确定作用机制并测量模型中神经元生存能力和功能的保存青光眼系统。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所需的临床前数据才能完成现有靶向人眼压的疗法。根据目前的阿尔茨海默氏症提出的研究以疾病（AD）为重点的行政补充应用程序将使我们能够在这些新颖的基础上建立临床前数据集，从而制定一种新型的治疗策略来保护受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神经元和受青光眼影响的视神经的神经元，缺乏 AD病理学导致的细胞防御机制降低了CNS的生存力和功能神经元可能会因父母的新理论策略而减弱奖。为此，将开发出一种新颖的干预方法，可以探索设计出可以通过保护广告影响的CNS神经元的新颖疗法来自氧化应激介导的损伤和功能丧失。三维（3D）生物印刷人类神经细胞构建体将用作AD的体外模型和AD中的药物发现以及采用与父母奖一致的实验策略的相关痴呆症。这提出的实验将确定目标的新颖理论策略的潜力 AD中的预防和神经保护疗法。创新策略有可能为AD生成第一类药物治疗方法。该策略的潜在高度影响在于其本质上具有预防性和治疗性的能力当前和未来的治疗设计和理由。