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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：
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
项目类别：
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

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

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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.