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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要/摘要糖尿病性视网膜病（DR）是美国工人成年人失明的主要原因。在糖尿病的个体，高血糖的持续时间和严重程度与发展视网膜病，长期以来一直被认为是导致发作博士的主要因素。但是高血糖导致DR病理学的机制尚不清楚。感受器都是最大的富含视网膜中最有活性的细胞，它们已被证明有助于 DR的发病机理，但感光受体对高血糖的反应仍然鲜为人知。我们的初步数据表明，活化T细胞（NFAT）的核因子的C2同工型显着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在体外用高葡萄糖处理的光感受器。 NFATC2靶基因包括已经显示以调节炎症和相关过程，驱动DR的进展。但是功能 NFATC2诱导在暴露于高葡萄糖的光感受器中的含义尚不清楚。假设该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促炎蛋白的诱导并减少感光体对其他的下游影响视网膜细胞类型，包括Müller神经胶质细胞和视网膜微血管内皮细胞。在博士的心态下约翰·佩恩（John Penn），该假设将通过逐步方法进行检验，完成原代细胞培养基于DR相关病理过程的体内小鼠模型（AIM 2）的基于基于的测定（AIM 1）。确认 NFAT抑制剂和NFATC2在感光体中功能丧失的能力降低DR的进展确认NFATC2作为该条件的治疗靶标的潜力。首席研究员是医学博士博士玻璃体外科医生的神经科学和临床培训的科学培训。 K08奖将利用她先前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，其中包括除了John Penn博士，Sabine Fuhrmann博士是神经元视网膜和残留颜料的专家上皮和系统性糖尿病专家Maureen Gannon博士。工作将在范德比尔特大学医学院的杰出科学与协作环境和范德比尔特大学医学中心（Vanderbilt University Medical Center），在成功临床方面拥有出色的记录科学家。 De La Huerta博士将开发必要的技能，成为该领域的独立调查员糖尿病性视网膜病的同时生成试验数据以成功竞争独立的NIH资金，促进对DR病理生理学博士的理解，并加速新的DR疗法的发展。