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: 10333217
• 负责人: Peter Koulen
• 金额: $ 37.59万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333217
• 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; 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; nerve damage; 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

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.

项目概要/摘要 该提案是对 NEI 战略计划的回应，NEI 最近在“视觉研究： 需求、差距和机会”，并重点介绍我们最新发现的一种新型神经元 根植于衰老与眼部疾病生物学机制交叉点的机制 作为高度计划优先事项。拟议的研究针对神经保护的新机制 利用细胞内钙通道作为药物靶点来治疗青光眼的神经变性。 具体来说，我们计划确定作用机制并测量神经元的保存 青光眼模型系统的活力和功能。拟议的研究将使我们能够产生 开发新型神经保护剂以补充现有疗法所需的临床前数据 目标眼压：视网膜神经节细胞的细胞内游离 Ca2+ 浓度，如 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出现失调。对于 急性和慢性退行性疾病的发展，包括青光眼，降低活力和 视网膜神经节细胞（RGC）的功能多项研究表明，细胞内第二个细胞的变化 信使浓度和细胞内 Ca2+ 浓度的病理性增加促进 发病。本申请将检验 RGC 的 Ca2+ 信号传导在功能上的假设 神经退行性损伤后，RGC 中立即早期基因产物上调，从而调节 产生细胞防御机制。该假设基于强有力的初步证据，即 视网膜的正常老化在机制上与青光眼疾病过程相似，可以加以利用 设计青光眼的新疗法。旨在检验这一假设的拟议实验将 研究这种相互作用背后的分子、细胞和功能机制 在青光眼模型中通过实验诱发疾病状况。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同时 本质上是预防性和治疗性的，并补充现有的治疗设计和原理。

项目成果

Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies.

• DOI: 10.4103/1673-5374.382220
• 发表时间: 2024-04
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Duncan RS;Riordan SM;Gernon MC;Koulen P
• 通讯作者: Koulen P

Novel Machine-Learning Based Framework Using Electroretinography Data for the Detection of Early-Stage Glaucoma.

• DOI: 10.3389/fnins.2022.869137
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Gajendran, Mohan Kumar;Rohowetz, Landon J.;Koulen, Peter;Mehdizadeh, Amirfarhang
• 通讯作者: Mehdizadeh, Amirfarhang

Analysis of Glaucoma Associated Genes in Response to Inflammation, an Examination of a Public Data Set Derived from Peripheral Blood from Patients with Hepatitis C.

• DOI: 10.2147/opth.s364739
• 发表时间: 2022
• 期刊: Clinical ophthalmology (Auckland, N.Z.)

N-acylethanolamide metabolizing enzymes are upregulated in human neural progenitor-derived neurons exposed to sub-lethal oxidative stress.

• DOI: 10.3389/fncel.2022.902278
• 发表时间: 2022
• 期刊: FRONTIERS IN CELLULAR NEUROSCIENCE
• 影响因子: 5.3
• 作者: Duncan, R. Scott;Riordan, Sean M.;Hall, Conner W.;Payne, Andrew J.;Chapman, Kent D.;Koulen, Peter
• 通讯作者: Koulen, Peter