Circadian Rhythms in Müller Cell Dysfunction

Müller 细胞功能障碍的昼夜节律

• 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
• 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' 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

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.

糖尿病性视网膜病（DR）是糖尿病的长期并发症。大约有700万美国人 患有这种威胁糖尿病的观察并发症。致病性的复杂性 DR的机制是缺乏承诺治疗DR的主要原因。穆勒 细胞是视网膜的主要神经胶质，由于其独特而在DR的发病机理中起关键作用 解剖位置跨越整个视网膜和专用功能，例如水和K+ 平衡，摄取神经递质和糖原储存。 müller细胞通过 内向纠正Kir4.1通道。在DR中，Müller细胞由于 Kir4.1通道的下调和水的积累。昼夜节律发挥 在管理身体的许多生化和身体功能方面的重要作用。昼夜节律 节奏破坏会导致胰岛素抵抗，肥胖和2型糖尿病（T2D）。以前使用 T2D大鼠，我们报道了DR的节奏调节时钟基因的功能失调。我们进一步 使用关键时钟重置基因PER2测试了DR中时钟的重要性，以表明 Per2m/m小鼠概括了与DR相似的表型特征。我们令人兴奋的初步研究 证明（i）kir4.1在视网膜中表现出昼夜节奏，而kir4.1的生物节律是 在糖尿病中抑制； （ii）KNCJ10（Kir4.1的基因）在时钟基因调节下； （iii） 通过胰岛素受体底物1（IRS-1）介导的胰岛素信号传导对于KIR4.1表达至关重要。 但是，关于受到干扰的昼夜节律的影响，知道有差距 müller细胞功能。因此，这项研究的目的是了解昼夜节律的作用 控制KIR4.1功能的调节机制并评估昼夜节律的方式 恢复纠正Müller细胞功能障碍。我们提出了昼夜节律的假设 心律不齐将改变KIR4.1表达导致Müller细胞功能障碍。我们建议 遵循特定的目的是检验我们的假设。目标1：确定该机制 功能失调的时钟与Müller细胞功能障碍有关。目标2：评估昼夜节律是否 节奏破坏使Müller细胞具有抗胰岛素信号的抗性。目标3：测试是否校正 DB/DB小鼠中的中央时钟可恢复Müller细胞功能障碍。这项研究的结果将 通过研究昼夜节律的参与来确定DR的新型致病机制 Müller细胞功能障碍中的节奏。昼夜节律的调节可能代表一本小说 医学博士管理的治疗策略。