Targeting the Etiology of Diabetic Retinopathy

针对糖尿病视网膜病变的病因

基本信息

批准号：
10270082
负责人：
Michael D. Dennis
金额：
$ 8.27万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10270082
关键词：
Address Adult Affect Age American Antioxidants Automobile Driving Binding Biological Models Blindness C-terminal Cell Culture Techniques Cells Centers for Disease Control and Prevention (U.S.)Clinical Trials Complement Complication Contrast Sensitivity DNA Damage Developed Countries Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Progression Early Intervention Edema Electroretinography Etiology Event Exposure to Functional disorder Gene Expression Genetic Transcription Grant Half-Life Human Hyperglycemia Impairment Individual Insulin-Dependent Diabetes Mellitus Laboratories Light Mediating Messenger RNA Microvascular Dysfunction Molecular Muller&apos s cell Mus Non-Insulin-Dependent Diabetes Mellitus Onset of illness Optical Coherence Tomography Oxidative Stress Parents Pathology Patients Prediabetes syndrome Proteins Protocols documentation Reading Research Retina Rodent Model Role S-nitro-N-acetylpenicillamine Small Interfering RNA Streptozocin TXN gene TXNIP gene Technical Expertise Techniques Testing Therapeutic Ubiquitination Vascular Endothelial Growth Factors Vision Visual Visual Acuity Visual Fields aged bevacizumab biological adaptation to stress clinically significant design diabetic diabetic patient doctoral student improved in vivo knock-down macular edema multicatalytic endopeptidase complex neovascularization novel therapeutics pre-clinical pre-doctoral prevent protein degradation protein expression skills training opportunity virtual visual dysfunction

项目摘要

PROJECT SUMMARY Diabetic retinopathy is the leading cause of blindness in working age Americans, affecting more than a third of the ~20 million individuals with diabetes. The project proposed for this research supplement to enhance diversity is designed to complement the aims of the parent R01 by examining the impact of diabetes on degradation of the stress response protein REDD1 (regulated in development and DNA damage 1) in the retina. Our laboratory has demonstrated that REDD1 expression is increased in the retina of diabetic mice, and is necessary for diabetes-induced retinal pathology and functional deficits in vision. Moreover, siRNA-mediated REDD1 knockdown improves best-corrected visual acuity in patients with diabetic macular edema. Thus, identification of the molecular events responsible for diabetes-induced REDD1 expression in the retina is of high clinical significance. In studies conducted as part of the Parental Grant, we recently found evidence that a post-transcriptional mechanism was potentially responsible for the increase in REDD1 protein in the retina of diabetic mice. Specifically, in the retina of streptozotocin-induced diabetic mice, REDD1 protein expression was increased in the absence of a change in REDD1 mRNA abundance. The central hypothesis of this supplement is that diabetes-induced oxidative stress promotes REDD1 interaction with TXNIP (thioredoxin interacting protein) in a manner that prevents the ubiquitination and subsequent proteasomal degradation of REDD1. To test the hypothesis, the applicant will pursue an experimental protocol involving model systems ranging from intact mice to retinal cell culture. Aim 1 will use cutting-edge molecular techniques (e.g. SNAP- tagging) to evaluate the impact of diabetes on retinal REDD1 protein degradation. Aim 2 will examine the impact of TXNIP on retinal REDD1 protein turnover in the context of diabetes. The specific mechanism(s) responsible for the increase in REDD1 that is associated with the diabetes-induced decline in visual function has not been previously established, and thus represents a significant gap in our understanding of the molecular events that cause visual dysfunction in diabetic retinopathy. Overall, the studies supported by this supplement will greatly enhance the parent R01 by exploring why hyperglycemic conditions promote retinal REDD1 protein content. The proposed project represents a focused thesis project that provides two key training opportunities for a promising pre-doctoral student. First, the applicant will develop the technical expertise to assess the impact of diabetes on retinal pathophysiology using optical coherence tomography, electroretinograms, and virtual optomotry. The applicant will also develop skills necessary to manipulate retinal gene expression in vivo using AAV.