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：
9916194
负责人：
Peter Koulen
金额：
$ 38.75万
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/9916194
关键词：
Acquired Immunodeficiency Syndrome Acute Affect Aging Animal Model Attenuated Biological Biological Models Biomimetics Blindness Calcium Channel Calcium Signaling Chronic Clinical Clinical Management Clinical Trials Combined Modality Therapy Complement Complex Data Defense Mechanisms Degenerative Disorder Development Disease Dominant-Negative Mutation Drug Targeting Eye diseases Glaucoma Goals Health Healthcare Heart Diseases Homeostasis Homer 1 Homer 1a Immediate-Early Genes In Vitro Intervention Malignant Neoplasms Measures Minority Modeling Molecular Nature Nerve Degeneration Neurons Neuroprotective Agents Operative Surgical Procedures Ophthalmology Optic Nerve Pathogenesis Pathologic Patients Performance Pharmacologic Substance Pharmacotherapy Physiologic Intraocular Pressure Physiological Plant Roots Population Pre-Clinical Model Process Protein Isoforms Proteins Publishing Research Retina Retinal Ganglion Cells Second Messenger Systems Severity of illness Signal Transduction Strategic Planning Structure Synaptic Transmission Targeted Research Testing Therapeutic Time Treatment Efficacy United States Vision Vision research Visual Visual impairment base cost design expectation experimental study functional restoration gene product health care delivery health disparity human disease improved in vivo ineffective therapies neuroprotection normal aging novel novel therapeutic intervention pre-clinical preservation prevent response restoration retinal damage retinal neuron side effect targeted treatment therapeutic target therapy design therapy outcome treatment strategy visual performance

Acquired Immunodeficiency Syndrome Acute Affect Aging Animal Model Attenuated Biological Biological Models Biomimetics Blindness Calcium Channel Calcium Signaling Chronic Clinical Clinical Management Clinical Trials Combined Modality Therapy Complement Complex Data Defense Mechanisms Degenerative Disorder Development Disease Dominant-Negative Mutation Drug Targeting Eye diseases Glaucoma Goals Health Healthcare Heart Diseases Homeostasis Homer 1 Homer 1a Immediate-Early Genes In Vitro Intervention Malignant Neoplasms Measures Minority Modeling Molecular Nature Nerve Degeneration Neurons Neuroprotective Agents Operative Surgical Procedures Ophthalmology Optic Nerve Pathogenesis Pathologic Patients Performance Pharmacologic Substance Pharmacotherapy Physiologic Intraocular Pressure Physiological Plant Roots Population Pre-Clinical Model Process Protein Isoforms Proteins Publishing Research Retina Retinal Ganglion Cells Second Messenger Systems Severity of illness Signal Transduction Strategic Planning Structure Synaptic Transmission Targeted Research Testing Therapeutic Time Treatment Efficacy United States Vision Vision research Visual Visual impairment base cost design expectation experimental study functional restoration gene product health care delivery health disparity human disease improved in vivo ineffective therapies neuroprotection normal aging novel novel therapeutic intervention pre-clinical preservation prevent response restoration retinal damage retinal neuron side effect targeted treatment therapeutic target therapy design therapy outcome treatment strategy visual performance

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项目摘要

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.

项目摘要/摘要该提案是对NEI最近在“视觉研究：需求，差距和机遇”，并专注于我们对新型神经元的最新发现扎根于衰老交汇处的机制和鉴定出眼病的生物学机制作为高计划优先级。拟议的研究针对神经保护的新机制使用细胞内钙通道作为药物靶标，以治疗青光眼中的神经退行性。具体而言，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中的生存力和功能。拟议的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疗法靶向眼压：视网膜神经节细胞的细胞内游离Ca2+浓度中枢神经系统的其他神经元受到高度调节，并且在衰老过程中会受到失调。为了急性和慢性变性疾病的发展，包括青光眼降低生存能力和视网膜神经节细胞（RGC）的功能几项研究表明，两种细胞内第二个变化细胞内Ca2+浓度的信使浓度和病理增加促进发病。本应用将检验以下假设，即RGC的Ca2+信号在功能上是神经退行性损伤后，由RGC中更新的早期基因产品调节产生一种细胞防御机制。该假设是基于有力的初步证据视网膜的正常衰老在机械上与青光眼疾病过程相似，可以被利用设计新颖的青光眼治疗方法。旨在检验此假设的拟议实验将研究这种相互作用下的分子，细胞和功能机制青光眼模型中实验引起的疾病状况。拟议的总体目标研究是确定一种新型RGC神经保护机制，并确定其作为策略的潜力用于针对RGC的神经保护疗法。这种疗法将有可能成为自然界的预防和治疗性，并补充现有的治疗设计和理由。