Molecular Mechanisms of Diabetic Retinal Ganglion Cell Dysfunction and Neurovascular Crosstalk in Early Diabetic Retinopathy

早期糖尿病视网膜病变中糖尿病视网膜神经节细胞功能障碍和神经血管串扰的分子机制

• 批准号: 10368046
• 负责人: Mira Menon Sachdeva
• 金额: $ 19.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368046
• 关键词: Address; Adult; Affect; Age; Animal Model; Award; Biogenesis; Blindness; Blood Vessels; Blood-Retinal Barrier; Characteristics; Clinical; Coculture Techniques; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Disease Pathway; Doctor of Philosophy; Equilibrium; Exhibits; Foundations; Functional disorder; Future; Glucose; Grant; Growth; Histology; Impairment; In Vitro; Inherited; Investigation; Laboratories; Link; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Mitochondria; Molecular; Mus; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Ophthalmology; Oxidative Stress; PINK1 gene; Parkin; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Play; Positioning Attribute; Principal Investigator; Process; Regulation; Repression; Research; Research Personnel; Retina; Retinal Diseases; Retinal Ganglion Cells; Retinal Neovascularization; Role; SECTM1 gene; Scientist; Streptozocin; Surgeon; Testing; Therapeutic; Thick; Training; Universities; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular Permeabilities; Visual; Work; angiogenesis; aqueous; base; clinical application; collaborative environment; diabetic; diabetic patient; dopaminergic neuron; human embryonic stem cell; in vitro Model; in vivo; in vivo Model; knock-down; macular edema; medical schools; mitochondrial dysfunction; mouse model; neuron loss; neuronal metabolism; neuroprotection; neurovascular; novel; potential biomarker; prevent; respiratory; retinal neuron; vascular endothelial dysfunction; visual dysfunction

PROJECT SUMMARY/ABSTRACT Diabetic retinopathy (DR) represents the leading cause of blindness in working-age adults, with vision loss due to sequelae of proliferative retinal neovascularization and diabetic macular edema (DME). As such, it has traditionally been considered a disease of the retinal microvasculature. However, diabetes is also associated with retinal neuronal damage and diabetic patients exhibit visual functional deficits prior to the onset of clinically-apparent retinopathy. Increasing evidence from both diabetic patients and mouse models has further demonstrated progressive inner retinal neuronal loss which is present early in the course of the disease, preceding clinically-identified retinal vascular changes. The molecular mechanisms of early diabetic retinal neurodegeneration are unknown, although mitochondrial dysfunction has been implicated in DR, primarily in studies of whole retina and vascular endothelial cells. Mitochondrial dysfunction has also been shown to play a critical role in the pathogenesis of neurodegeneration in Parkinson’s disease (PD), with rare hereditary forms of PD associated with mutations in the mitophagy genes PINK1 and parkin. The laboratory of Dr. Ted Dawson, the principal investigator’s primary mentor, has identified a novel parkin-interacting substrate, PARIS, which regulates mitochondrial biogenesis via repression of PGC1a and has demonstrated that loss of dopaminergic neurons in the setting of parkin deficiency is driven primarily by impairments in mitochondrial biogenesis via the parkin/PARIS/PGC1a pathway. The role of mitochondrial biogenesis and its balance with mitophagy in retinal ganglion cells (RGCs) under diabetic conditions has not been explored. The hypotheses of this project are that (1) diabetes directly induces RGC dysfunction and loss via perturbations in the parkin/PARIS/PGC1a pathway of mitochondrial mass regulation, and that (2) dysfunctional RGCs in this setting secrete factors that directly affect the retinal vasculature. Under the additional mentorship of Dr. Don Zack and Dr. Gerard Lutty, and within the rich collaborative environment of the Johns Hopkins University School of Medicine, these hypotheses will be tested using in vitro approaches with primary cultured murine RGCs and hESC-derived RGCs, and in an in vivo mouse model of diabetes (streptozocin). The principal investigator is an MD/PhD clinician-scientist, who completed her training as a Vitreoretinal Surgeon, and now regularly cares for patients with vision loss due to diabetic retinal disease despite currently-available treatments, motivating her to investigate novel molecular pathways of disease pathogenesis. She is currently in year one of support from the Johns Hopkins Department of Ophthalmology K12 grant. Building upon the foundation of her PhD research, this K08 award will facilitate the additional expertise and training she needs to address her hypotheses and eventually transition to a position as an independent investigator in retinal neuronal metabolism, retinal neuroprotection, and neurovascular crosstalk.

项目总结/摘要 糖尿病视网膜病变（DR）是工作年龄成人失明的主要原因， 增殖性视网膜新生血管和糖尿病性黄斑水肿（DME）的后遗症。因此， 传统上被认为是视网膜微血管疾病。然而，糖尿病也与 视网膜神经元损伤和糖尿病患者表现出视觉功能缺陷之前， 临床上明显的视网膜病变。来自糖尿病患者和小鼠模型的越来越多的证据表明， 表现出进行性视网膜内神经元丧失，这在疾病过程的早期就存在， 在临床上确定的视网膜血管变化之前。早期糖尿病视网膜病变的分子机制 神经变性是未知的，尽管线粒体功能障碍与DR有关，主要是在 整个视网膜和血管内皮细胞的研究。线粒体功能障碍也被证明是 在帕金森病（PD）神经变性的发病机制中起关键作用，具有罕见的遗传形式 与线粒体自噬基因PINK1和parkin突变相关的PD。泰德博士的实验室 道森，首席研究员的主要导师，已经确定了一种新的帕金森相互作用的底物，巴黎， 它通过抑制PGC1a来调节线粒体的生物合成，并且已经证明， 多巴胺能神经元在帕金缺乏的情况下主要是由线粒体损伤驱动的。 通过parkin/PARIS/PGC1a途径进行生物合成。线粒体生物合成的作用及其与 糖尿病条件下视网膜神经节细胞（RGC）中的线粒体自噬尚未被探索。的假设 本项目的主要结论是：（1）糖尿病直接诱导RGC功能障碍和损失， parkin/PARIS/PGC1a途径的线粒体质量调节，以及（2）在此过程中功能失调的RGC 设置分泌的因素，直接影响视网膜血管。在唐博士的额外指导下 Zack和Gerard Lutty博士，在约翰霍普金斯大学丰富的合作环境中， 医学院，这些假设将使用原代培养的小鼠体外方法进行测试 RGC和hESC衍生的RGC，以及体内糖尿病小鼠模型（链脲霉素）。校长 研究者是一名医学博士/博士临床科学家，她完成了玻璃体视网膜外科医生的培训，现在 定期护理因糖尿病视网膜疾病而导致视力丧失的患者， 治疗，激励她研究疾病发病机制的新分子途径。她目前正在 在约翰霍普金斯眼科K12基金的支持下，的基础上继续努力 作为她博士研究的基础，这个K08奖将促进她所需的额外专业知识和培训， 解决她的假设，并最终过渡到视网膜病变的独立研究者的位置， 神经元代谢、视网膜神经保护和神经血管串扰。