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: 10613428
• 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/10613428
• 关键词: Academic Medical Centers; Acceleration; Address; Adult; Age; Animal Model; Authorization documentation; Automobile Driving; Award; Biological Assay; Biostatistical Methods; Blindness; Blood Vessels; Cell Nucleus; Cells; Cellular biology; Complement; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Doctor of Medicine; Doctor of Philosophy; 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; 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; Vascular Endothelial Cell; Work; authority; cell type; clinical training; 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.

项目总结/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，高血糖症的持续时间和严重程度与以下风险相关： 发展为视网膜病变，长期以来被认为是导致DR发病的主要因素。然而 高血糖症导致DR病理的机制尚不清楚。光感受器都是 丰富和最代谢活跃的细胞在视网膜上，他们已被证明有助于 糖尿病视网膜病变的发病机制，但光感受器对高血糖的反应仍然知之甚少。我们 初步数据表明，活化T细胞核因子（NFAT）的c2同种型显著增加， 在体内暴露于高血糖的光感受器中诱导，并被激活并易位到细胞核 高浓度葡萄糖处理的光感受器。NFATc 2靶基因包括已经被证实的细胞因子。 显示调节炎症和驱动DR进展的相关过程。 暴露于高葡萄糖的光感受器中NFATc 2诱导的意义尚不清楚。的假设 该项目是在高血糖条件下特异性抑制光感受器中的NFATc 2可以减少 促炎蛋白的诱导和减少光感受器对其他细胞的下游作用， 视网膜细胞类型，包括Müller神经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，这个假设将用逐步的方法进行测试，补充原代细胞培养- 使用DR相关病理过程的体内小鼠模型（目的2）进行基于试验（目的1）的研究。确认 NFAT抑制剂和NFATc 2在光感受器中的功能丧失减少DR进展的能力将 证实NFATc 2作为这种病症的治疗靶点的潜力。主要研究者是医学博士。 博士他是一名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生兼科学家。 K 08奖将利用她之前在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的经验，包括 除了John Penn博士，Sabine Fuhrmann博士是神经视网膜和视网膜色素的专家 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杰出的科学和协作环境， 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出色的记录- 科学家德拉韦尔塔博士将发展必要的技能，成为该领域的独立调查员 糖尿病视网膜病变，同时产生试点数据，以成功地竞争独立的国家卫生研究院的资金， 促进对DR病理生理学的理解，并加速新DR疗法的开发。