Neuroprotection in pediatric retinal detachment

小儿视网膜脱离的神经保护

• 批准号: 9247204
• 负责人: Cagri Besirli
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247204
• 关键词: Animal Model; Animals; Apoptosis; Apoptotic; Appointment; Area; Bioinformatics; Biotechnology; Blindness; Blood Vessels; Brain-Derived Neurotrophic Factor; Caregivers; Cell Death; Cessation of life; Characteristics; Child; Childhood; Ciliary Neurotrophic Factor; Clinical; Developed Countries; Developing Countries; Disease; Environment; Etiology; Exudate; Eye; Faculty; Goals; Hemorrhage; Human; Inherited; Institutes; Ischemia; Life; Lipids; Liquid substance; Mentors; Michigan; Modeling; Operative Surgical Procedures; Ophthalmology; Pathway interactions; Patients; Photoreceptors; Physicians; Proteins; Proteomics; Public Health; Quality of life; Recovery; Research; Research Proposals; Resolution; Retina; Retinal; Retinal Degeneration; Retinal Detachment; Retinal Diseases; Retinal Hemorrhage; Retinal Photoreceptors; Retinopathy of Prematurity; Rodent; Rodent Model; Sampling; Scientist; Secondary to; Services; Specialist; Structure of retinal pigment epithelium; Testing; Therapeutic Agents; Tin; Toxic effect; Training; Translating; Universities; Vision; Visual; Work; design; experience; experimental study; improved; member; neuroprotection; novel; novel therapeutics; pediatric patients; prevent; productivity loss; programs; public health relevance; repaired; research study; restoration; retinal ischemia; success; tool; vision science

DESCRIPTION (provided by applicant): Pediatric retinal detachment is a leading cause of childhood blindness in developed countries. One of the common characteristics of inherited or acquired pediatric retinal detachments is the subretinal exudation of fluid, hemorrhage and lipid, causing separation of photoreceptors from the retinal pigment epithelium (RPE) and the death of photoreceptors. However, a significant portion of children re-gain limited vision once the retina re-attaches after the resolution of subretinal exudate, which indicates that some photoreceptors are able to survive the prolonged separation from the RPE. The primary aim of this research study is to characterize the neuroprotective pathways regulating the survival mechanisms to keep photoreceptors alive despite persistent ischemia and toxicity. The long-term goal of this work is to design therapeutic agents to enhance intrinsic neuroprotective pathways to improve visual recovery. The over-arching hypothesis we are using to formulate this research proposal is that activation of retinal neuroprotective pathways inhibit photoreceptor apoptosis and prevent outer retinal degeneration during periods of pediatric exudative retinal detachment. We are proposing to identify these neuroprotective pathways using clinical samples from pediatric patients with exudative retinal detachment and characterizing them in a rodent model of exudative retinal detachment. We will test our central hypothesis with three specific aims: 1) Targeted analysis of retinal neuroprotective factors in pediatric exudative retinal detachment; 2) Functional analysis of neuroprotective proteins in rodent subretinal hemorrhage, an animal model for exudative retinal detachment; 3) Identification of novel neuroprotective and apoptotic pathways activated in pediatric exudative retinal detachment using human proteomics. My academic appointment as a pediatric retina specialist provides the ideal environment to translate clinical problems into research questions and transform research findings into clinical tools. As a faculty member at the University of Michigan, my clinical duties will include treating children with pediatric retinal disorders and my research program will explore the neuroprotective networks that regulate photoreceptor survival in diseased retinas. My ultimate goal as a physician-scientist is to develop new therapeutic agents to improve vision in children with retinal diseases. The Department of Ophthalmology and Visual Sciences and the University of Michigan has a world-class faculty and facilities. I will benefit from thoughtful "hands-on" mentoring by experienced scientists and clinicians who are deeply committed to my success. This training will be further enhanced by my interaction with the leading experts in the field of pediatric retina from Oakland University and Beaumont Eye Institute. Some of the proposed experiments involve the use of proteomics and bioinformatics. The new expertise gained in these areas through hands-on biotechnology training courses and didactic sessions will allow me to apply the power of proteomics to pediatric retinal diseases.

描述（由申请人提供）：在发达国家，儿童视网膜脱离是儿童失明的主要原因。遗传性或获得性小儿视网膜脱离的共同特征之一是视网膜下渗出液体、出血和脂质，导致光感受器与视网膜色素上皮（RPE）分离和光感受器死亡。然而，一旦视网膜下渗出物消退后视网膜重新附着，很大一部分儿童重新获得有限的视力，这表明一些光感受器能够在与RPE长时间分离后存活。这项研究的主要目的是表征神经保护途径调节生存机制，以保持光感受器存活，尽管持续缺血和毒性。这项工作的长期目标是设计治疗剂，以增强内在的神经保护途径，以改善视力恢复。 我们用来制定这项研究计划的过度假设是，视网膜神经保护通路的激活抑制了感光细胞的生长， 细胞凋亡和预防儿童渗出性视网膜脱离期间的外视网膜变性。我们建议使用渗出性视网膜脱离儿科患者的临床样本识别这些神经保护途径，并在渗出性视网膜脱离的啮齿动物模型中对其进行表征。我们将通过三个具体目标来验证我们的中心假设：1）针对儿童渗出性视网膜脱离中视网膜神经保护因子的靶向分析; 2）啮齿动物视网膜下出血（渗出性视网膜脱离的动物模型）中神经保护蛋白的功能分析; 3）使用人类蛋白质组学鉴定儿童渗出性视网膜脱离中激活的新型神经保护和凋亡途径。 我作为一名儿科视网膜专家的学术任命提供了理想的环境，将临床问题转化为研究问题，并将研究结果转化为临床工具。作为密歇根大学的一名教员，我的临床职责 将包括治疗儿童视网膜疾病，我的研究计划将探索神经保护网络，调节感光细胞在患病视网膜的生存。作为一名医生和科学家，我的最终目标是开发新的治疗药物，以改善患有视网膜疾病的儿童的视力。密歇根大学眼科和视觉科学系拥有世界一流的师资和设施。我将受益于经验丰富的科学家和临床医生的周到的“动手”指导，他们深深致力于我的成功。通过我与奥克兰大学和博蒙眼科研究所的儿科视网膜领域的领先专家的互动，这一培训将得到进一步加强。一些拟议的实验涉及使用蛋白质组学和生物信息学。通过动手生物技术培训课程和教学课程在这些领域获得的新专业知识将使我能够将蛋白质组学的力量应用于儿科视网膜疾病。