Mechanisms of Photoreceptor Contribution to Retinal Inflammation in Diabetic Retinopathy

光感受器对糖尿病视网膜病变视网膜炎症的作用机制

• 批准号: 10394925
• 负责人: Irina De la Huerta
• 金额: $ 20.78万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394925
• 关键词: Academic Medical Centers; Address; Adult; Age; Animal Model; Automobile Driving; Award; Biological Assay; Biostatistical Methods; Blindness; Blood Vessels; Cell Nucleus; Cells; Cellular biology; Clinical; Complement; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Doctor of Medicine; Doctor of Philosophy; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Exposure to; Functional disorder; Funding; Genes; Glucose; Goals; Hyperglycemia; In Vitro; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 alpha; Intervention; Knockout Mice; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Muller' s cell; Mus; Neural Retina; Neuroglia; Neurosciences; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Permeability; Photoreceptors; Physicians; Prevalence; Primary Cell Cultures; Principal Investigator; Process; Production; Protein Isoforms; Proteins; Research; Research Personnel; Retina; Retinal Diseases; Retinal Photoreceptors; Rhodopsin; Risk; Role; Scientist; Severities; Small Interfering RNA; Specialist; Streptozocin; Structure of retinal pigment epithelium; Surgeon; TNF gene; Techniques; Testing; Therapeutic; Training; United States; United States National Institutes of Health; Universities; Vascular Diseases; Work; authority; base; cell type; collaborative environment; cytokine; diabetic patient; experience; in vitro Assay; in vivo; inhibitor; loss of function; medical schools; monolayer; mouse model; nuclear factors of activated T-cells; prevent; programs; promoter; response; skills; transcription factor; vision development

Project Summary/Abstract Diabetic retinopathy (DR) is the principal cause of blindness among working-age adults in the United States. In individuals with diabetes mellitus, the duration and the severity of hyperglycemia correlate with the risk of developing retinopathy, and have long been considered the main factors leading to DR onset. However the mechanism by which hyperglycemia leads to DR pathology is not known. Photoreceptors are both the most abundant and the most metabolically active cells in the retina, and they have been shown to contribute to the pathogenesis of DR, but the photoreceptor response to hyperglycemia remains poorly understood. Our preliminary data suggests that the c2 isoform of nuclear factor of activated T-cells (NFAT) is significantly induced in photoreceptors exposed to hyperglycemia in vivo, and is activated and translocates to the nucleus of photoreceptors treated with high glucose in vitro. NFATc2 target genes include cytokines that have been shown to regulate inflammation and related processes driving the progression of DR. However the functional implications of NFATc2 induction in photoreceptors exposed to high glucose are not known. The hypothesis of this project is that specific inhibition of NFATc2 in photoreceptors under hyperglycemic conditions can reduce the induction of pro-inflammatory proteins and decrease the downstream effects of photoreceptors on other retinal cell types, including Müller glia and retinal microvascular endothelial cells. Under the mentorship of Dr. John Penn, this hypothesis will be tested using a stepwise approach, complementing primary cell culture- based assays (Aim 1) with in vivo mouse models of DR-relevant pathologic processes (Aim 2). Confirming the ability of NFAT inhibitors and NFATc2 loss of function in photoreceptors to reduce the progression of DR will affirm the potential of NFATc2 as a treatment target for this condition. The principal investigator is an M.D. Ph.D. physician-scientist with scientific training in neuroscience and clinical training as a vitreoretinal surgeon. The K08 award will leverage her prior training under the mentorship of a world-class team with extensive experience in retinal vascular disease, retinal cell biology, and animal models of diabetes, and that includes, in addition to Dr. John Penn, Dr. Sabine Fuhrmann an expert in the neural retina and the retinal pigment epithelium, and Dr. Maureen Gannon, an expert in systemic diabetes. The work will take place within the outstanding scientific and collaborative environment of the Vanderbilt University School of Medicine and Vanderbilt University Medical Center, which have an excellent track record of producing successful clinician- scientists. Dr. De la Huerta will develop the necessary skills to become an independent investigator in the field of diabetic retinopathy, while generating pilot data to successfully compete for independent NIH funding, to advance the understanding of DR pathophysiology and to accelerate the development of new DR therapies.

项目概要/摘要 糖尿病视网膜病变（DR）是美国工作年龄成年人失明的主要原因。在 对于糖尿病患者来说，高血糖的持续时间和严重程度与以下风险相关： 视网膜病变，长期以来一直被认为是导致 DR 发病的主要因素。然而 高血糖导致 DR 病理的机制尚不清楚。光感受器是最 视网膜中含有丰富且代谢最活跃的细胞，它们已被证明有助于 DR 的发病机制，但光感受器对高血糖的反应仍知之甚少。我们的 初步数据表明，活化 T 细胞核因子 (NFAT) 的 c2 亚型显着 在体内暴露于高血糖的光感受器中被诱导，并被激活并转移到细胞核 体外用高葡萄糖处理的光感受器。 NFATc2 靶基因包括已被 显示可调节炎症和驱动 DR 进展的相关过程。然而功能性的 NFATc2 诱导对暴露于高葡萄糖的光感受器的影响尚不清楚。的假设 该项目的目的是在高血糖条件下特异性抑制光感受器中的 NFATc2 可以减少 诱导促炎蛋白并减少光感受器对其他细胞的下游影响 视网膜细胞类型，包括米勒胶质细胞和视网膜微血管内皮细胞。在博士的指导下 约翰·佩恩（John Penn），这一假设将使用逐步方法进行测试，补充原代细胞培养- 基于 DR 相关病理过程（目标 2）的体内小鼠模型的测定（目标 1）。确认 NFAT 抑制剂和 NFATc2 光感受器功能丧失减缓 DR 进展的能力将 肯定了 NFATc2 作为这种疾病治疗靶点的潜力。主要研究者是医学博士。 博士接受过神经科学科学培训和玻璃体视网膜外科医生临床培训的医师科学家。 K08 奖将利用她之前在一个拥有广泛知识的世界级团队的指导下接受的培训 在视网膜血管疾病、视网膜细胞生物学和糖尿病动物模型方面拥有丰富的经验，其中包括 除了 John Penn 博士之外，Sabine Fuhrmann 博士也是神经视网膜和视网膜色素方面的专家 上皮细胞和系统性糖尿病专家 Maureen Gannon 博士。这项工作将在 范德比尔特大学医学院出色的科学和协作环境 范德比尔特大学医学中心在培养成功的临床医生方面拥有良好的记录- 科学家。 De la Huerta 博士将培养成为该领域独立调查员所需的技能 糖尿病视网膜病变的研究，同时生成试点数据以成功竞争独立的 NIH 资金， 增进对 DR 病理生理学的理解并加速新 DR 疗法的开发。