Muller glial dysfunction in retinal edema

视网膜水肿中的 Muller 胶质细胞功能障碍

• 批准号: 9767196
• 负责人: Michael John Allingham
• 金额: $ 15.97万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767196
• 关键词: Adrenal Cortex Hormones; Adult; Affect; Animal Model; Area; Automobile Driving; Award; Biological Models; Biology; Blindness; Blood; Blood Vessels; Blood capillaries; Clinical; Clinical Research; Cyst; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diffuse; Disadvantaged; Disease; Doctor of Medicine; Doctor of Philosophy; Ensure; Environment; Event; Extracellular Fluid; Extravasation; Eye; Faculty; Failure; Functional disorder; Funding; Goals; Health; Hemorrhage; Human; Inflammation; Injections; Injury; Intracellular Fluid; Ischemia; Lasers; Liquid substance; Medical; Mentors; Mitochondria; Modeling; Muller' s cell; Mus; Nature; Neurobiology; Neuroglia; Ophthalmology; Pathogenesis; Pathology; Patients; Peptides; Pharmaceutical Preparations; Potassium; Prevention; Process; Program Development; Public Health; Publications; Pump; Recovery; Research; Retina; Retinal; Retinal Diseases; Retinal Edemas; Retinal Vein Occlusion; Risk; Role; SECTM1 gene; Scientist; Signal Transduction; Specialist; Structure; Study models; Supporting Cell; Swelling; Testing; Tissues; Training; United States; Universities; Uveitis; Vascular Endothelial Growth Factors; Vision; Water; Work; aged; base; career development; cost; diabetic; experience; eye center; faculty research; health goals; improved; in vivo; macula; macular edema; meetings; mitochondrial dysfunction; mouse model; new therapeutic target; novel; novel therapeutics; programs; public health relevance; responsible research conduct; retina blood vessel structure; side effect; success; vein occlusion

 DESCRIPTION (provided by applicant): The candidate is a retina trained clinician scientist who's clinical and research focus is improving treatments for patients suffering from retinal edema. To achieve his goal he will elucidate the mechanisms of retinal edema with a specific focus on the role of Müller glia (MG) and will generate and utilize animal models to identify and validate novel targets for therapy. He has completed an M.D./Ph.D., clinical training as a medical retina specialist and is currently one year into a two year commitment to the Duke Eye Center NEI K12 Career Development Program. During his first year as a K12 scholar, he has developed and begun to characterize a mouse laser-induced retinal vein occlusion (RVO) model for the study of retinal edema pathobiology. The candidate has chosen to study the causes of MG pump dysfunction, the failure of MG to transport fluid out of the retinal tissue. His immediate focus outlined in this proposal will be 1) understanding mechanisms driving MG pump dysfunction and swelling in retinal edema and 2) determining the role of RVO- induced MG mitochondrial dysfunction in this process. The candidate plans to submit an R01 early in his final year of K08 support that will utilize in vivo and ex vivo model systems and data generated during this proposal as a spring board to investigate the specific signaling events causing MG pump dysfunction. Additional didactic training in neurobiology and vascular biology, departmental research seminars, and advanced responsible conduct of research will be obtained during the award period, and the candidate will present his findings at national meetings and submit his work for publication. Environment: The candidate will have access to the world class clinical and research faculty of Duke's Department of Ophthalmology and will benefit more broadly from the intellectual environment present at Duke University. The mentoring team is comprised of experienced faculty who possess the necessary expertise to assist the candidate in accomplishing the proposed research. The significant institutional commitment on the part of the Departments of Ophthalmology and Neurobiology and ongoing mentoring from scientists and clinicians who are dedicated to his long term success will ensure a successful transition to an independent R01-funded research program. Research: Retinal edema (RE) causes vision loss in numerous retinal disorders including diabetes, vein occlusion, and uveitis. While anti-vascular endothelial growth factor agents and corticosteroids often improve RE, they are not universally effective, often resulting in incomplete vision recovery. Retinal edema results from a combination of leaking retinal blood vessels and loss of MG pump function which removes fluid from the retina. The central hypothesis is that cysts seen in RE represent swollen MG and that this swelling is caused by inability of MG to export fluid, termed MG pump dysfunction. To explore our conceptual hypothesis, we have developed a mouse model of cystic RE in experimental laser-induced retinal vein occlusion (RVO). Preliminary data demonstrate that RVO produces retinal thickening and development of cystic spaces in the retina. MG in the RVO-affected area show redistribution of water (AQP4) and potassium (Kir4.1) channels and increased cellular cross sectional area, suggesting intracellular fluid accumulation. These features occur in association with mitochondrial dysfunction, and we find that prevention of mitochondrial dysfunction reduces AQP4/Kir4.1 redistribution. Based on these observations, the model of RVO-induced retinal edema will be used to test two specific hypotheses (1) AQP4/ Kir4.1 redistribution following RVO causes MG swelling, which is driven by the inability of MG to export imbibed fluid; and (2) RVO causes MG mitochondrial dysfunction resulting in AQP4/Kir4.1 redistribution and MG pump dysfunction.

 描述（由申请人提供）：候选人是一名受过视网膜培训的临床科学家，其临床和研究重点是改善视网膜水肿患者的治疗。为了实现他的目标，他将阐明视网膜水肿的机制，特别关注Müller胶质细胞（MG）的作用，并将生成和利用动物模型来识别和验证新的治疗靶点。他完成了一个M.D./哲学博士、临床培训作为一个医学视网膜专家，目前是一年到为期两年的承诺，杜克眼科中心NEI K12职业发展计划。在他作为K12学者的第一年，他开发并开始表征用于视网膜水肿病理学研究的小鼠激光诱导视网膜静脉阻塞（RVO）模型。该候选人选择研究MG泵功能障碍的原因，即MG无法将液体从视网膜组织中输送出来。他在该提案中概述的直接重点将是1）理解驱动MG泵功能障碍和视网膜水肿肿胀的机制，以及2）确定RVO诱导的MG线粒体功能障碍在该过程中的作用。候选人计划在其K 08支持的最后一年早期提交R 01，该R 01将利用体内和离体模型系统以及本提案期间生成的数据作为跳板，以研究导致MG泵功能障碍的特定信号事件。在授予期间，将获得神经生物学和血管生物学，部门研究研讨会和先进的负责任的研究行为的额外教学培训，候选人将在全国会议上介绍他的研究结果，并提交他的工作出版。工作环境：候选人将有机会接触到杜克眼科世界级的临床和研究人员，并将从杜克大学的学术环境中受益。指导团队由经验丰富的教师组成，他们拥有必要的专业知识，以帮助候选人完成拟议的研究。眼科和神经生物学部门的重要机构承诺以及致力于他长期成功的科学家和临床医生的持续指导将确保成功过渡到独立的R 01资助的研究计划。研究：视网膜水肿（RE）导致许多视网膜疾病，包括糖尿病，静脉阻塞和葡萄膜炎的视力丧失。虽然抗血管内皮生长因子药物和皮质类固醇通常可以改善RE，但它们并不是普遍有效的，通常会导致视力恢复不完全。视网膜水肿是由视网膜血管渗漏和MG泵功能丧失（其从视网膜移除液体）的组合引起的。中心假设是RE中所见的囊肿代表MG肿胀，并且这种肿胀是由于MG不能输出液体引起的，称为MG泵功能障碍。为了探索我们的概念性假设，我们已经开发了一个小鼠模型的囊性RE在实验性激光诱导的视网膜静脉阻塞（RVO）。初步数据表明，RVO产生视网膜增厚和视网膜中囊性空间的发展。RVO影响区域的MG显示水（AQP 4）和钾（Kir4.1）通道的重新分布以及细胞横截面积增加，表明细胞内液蓄积。这些特征与线粒体功能障碍有关，我们发现预防线粒体功能障碍可减少AQP 4/Kir4.1再分布。基于这些观察结果，RVO诱导的视网膜水肿模型将用于检验两个特定假设：（1）RVO后AQP 4/ Kir4.1重新分布导致MG肿胀，这是由MG无法输出吸入的液体驱动的;和（2）RVO导致MG线粒体功能障碍，导致AQP 4/Kir4.1重新分布和MG泵功能障碍。