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Circadian Rhythms in Müller Cell Dysfunction

Müller 细胞功能障碍的昼夜节律

基本信息

批准号：
10186751
负责人：
Ashay D Bhatwadekar
金额：
$ 38.19万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186751
关键词：
ARNTL gene Adult Affect American Americas Anatomy Animal Model Arrhythmia Binding Biochemical Biological Assay Biological Markers Bioperiodicity Blindness Cell physiology Circadian Dysregulation Circadian Rhythms Complex Complications of Diabetes Mellitus Diabetes Mellitus Diabetic Retinopathy Disease Diurnal Rhythm Down-Regulation Electroretinography Equilibrium Exhibits Functional disorder Gene Expression Regulation Genes Genome Glycogen Individual Insulin Insulin Resistance Knowledge Light Link Measures Mediating Metabolic syndrome Monitor Motor Activity Muller&apos s cell Mus Nature Neuroglia Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Outcome Study Pathogenesis Pathogenicity Pattern Phenotype Physiological Plasma Play Positioning Attribute Rattus Regulation Regulator Genes Reporting Research Resistance Retina Rodent Model Role Sleep Sleep Deprivation Swelling Testing Time Vision Visual impairment Water circadian circadian regulation db/db mouse diabetes management diabetic glucose tolerance insulin receptor substrate 1 protein insulin signaling neurotransmitter uptake novel promoter restoration suprachiasmatic nucleus treatment strategy

项目摘要

Diabetic retinopathy (DR) is a long-term complication of diabetes. Around 7 million Americans are suffering from this sight-threatening complication of diabetes. The complex nature of pathogenic mechanisms of DR is the major reason for a lack of promising treatments to treat DR. The Müller cell, a major glia of the retina, plays a critical role in the pathogenesis of DR due to its unique anatomic position spanning the entire retina and the specialized functions such as water and K+ balance, uptake of neurotransmitters, and glycogen storage. Müller cells regulate K+ balance via inwardly rectifying Kir4.1 channels. In DR, the Müller cells are dysfunctional and swollen due to downregulation of Kir4.1 channels and accumulation of water. Circadian rhythms play an important role in governing many biochemical and physiological functions of the body. Circadian rhythm disruption leads to insulin resistance, obesity, and type 2 diabetes (T2D). Previously, using T2D rats, we reported a dysfunctional pattern of rhythm regulatory clock genes in DR. We further tested the importance of clock in DR using a critical clock resetting gene Per2 to show that the Per2m/m mice recapitulate phenotypic features similar to DR. Our exciting preliminary studies demonstrate that (i) Kir4.1 exhibits a diurnal rhythm in the retina and this biorhythm of Kir4.1 is dampened in diabetes; (ii) Kncj10 (the gene for Kir4.1) is under clock gene regulation; and (iii) insulin signaling mediated via insulin receptor substrate 1 (IRS-1) is critical for Kir4.1 expression. However, there is a gap in knowledge with regard to how a disturbed circadian rhythm influences Müller cell function. Therefore, the objective of this study is to understand the role of the circadian regulatory mechanism in controlling Kir4.1 function and to evaluate how circadian rhythm restoration corrects Müller cell dysfunction. We propose the hypothesis that circadian arrhythmia will alter Kir4.1 expression leading to a Müller cell dysfunction. We propose the following specific aims to test our hypothesis. Aim 1: To determine the mechanism by which the dysfunctional clock is involved in Müller cell dysfunction. Aim 2: To assess whether circadian rhythm disruption renders Müller cells resistant to the insulin signal. Aim 3: To test if correction of central clock in db/db mice restores the Müller cell dysfunction. The outcome of this study will ascertain a novel pathogenic mechanism of DR by studying the involvement of disturbed circadian rhythms in Müller cell dysfunction. Modulation of circadian rhythms may represent a novel treatment strategy for the management of DR.