Mechanisms of Photoreceptor Contribution to Retinal Inflammation in Diabetic Retinopathy

项目摘要/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……里面 糖尿病患者，高血糖的持续时间和严重程度与 发展中的视网膜病变，长期以来被认为是导致DR发病的主要因素。然而， 高血糖导致DR病理的机制尚不清楚。光感受器都是最 视网膜中丰富和代谢最活跃的细胞，它们被证明对 DR的发病机制，但光感受器对高血糖的反应仍然知之甚少。我们的 初步数据表明，活化T细胞核因子(NFAT)的c2亚型显著 在体内暴露于高血糖的光感受器中被诱导，并被激活并移位到细胞核 在体外用高糖处理的光感受器。NFATc2靶基因包括已被 被证明调节炎症和相关的过程，推动DR的进展，然而，功能 NFATc2在暴露于高糖的光感受器中的诱导作用尚不清楚。的假说 本项目是在高血糖条件下对光感受器中NFATc2的特异性抑制可以减少 诱导促炎蛋白和减少光感受器对其他 视网膜细胞类型，包括Müler胶质细胞和视网膜微血管内皮细胞。在博士的指导下。 约翰·潘，这一假设将用循序渐进的方法进行检验，以补充原代细胞培养- 以DR相关病理过程的小鼠体内模型为基础的检测(目标1)(目标2)。确认 NFAT抑制剂和光感受器NFATc2功能丧失减缓DR Will进展的能力 确认NFATc2作为这种疾病的治疗靶点的潜力。首席调查员是医学博士。 作为玻璃体视网膜外科医生，受过神经科学和临床训练的博士、内科医生和科学家。 K08奖将利用她之前在世界级团队的指导下接受的培训，该团队拥有广泛的 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有经验，包括 除了约翰·潘博士外，萨宾·富尔曼博士还是神经视网膜和视网膜色素方面的专家 以及系统性糖尿病专家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合作环境 范德比尔特大学医学中心，它们在培养成功的临床医生方面有着良好的记录- 科学家。德拉韦尔塔博士将培养必要的技能，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，成功竞争独立的NIH资金，以 增进对DR病理生理学的认识，促进DR新疗法的发展。

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.