Circadian Rhythms in Müller Cell Dysfunction

糖尿病视网膜病变（DR）是糖尿病的长期并发症。大约 700 万美国人 患有这种威胁视力的糖尿病并发症。病原体的复杂性 DR 的机制是缺乏有希望的 DR 治疗方法的主要原因。穆勒 细胞是视网膜的主要胶质细胞，由于其独特的特性，在 DR 的发病机制中发挥着关键作用。 跨越整个视网膜的解剖位置以及水和 K 等特殊功能 平衡、神经递质的摄取和糖原的储存。穆勒细胞通过调节钾平衡 内向整流Kir4.1通道。在 DR 中，Müller 细胞功能失调且肿胀，原因是 Kir4.1 通道的下调和水的积累。昼夜节律发挥着 在控制身体的许多生化和生理功能中发挥着重要作用。昼夜节律 节律紊乱会导致胰岛素抵抗、肥胖和 2 型糖尿病 (T2D)。以前，使用 我们报道了 T2D 大鼠 DR 中节律调节时钟基因的功能失调模式。我们进一步 使用关键时钟重置基因 Per2 测试了时钟在 DR 中的重要性，以表明 Per2m/m 小鼠重现了与 DR 相似的表型特征。我们激动人心的初步研究 证明 (i) Kir4.1 在视网膜中表现出昼夜节律，并且 Kir4.1 的生物节律是 糖尿病患者受到抑制； (ii) Kncj10（Kir4.1 的基因）受时钟基因调控； (三) 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。 然而，对于昼夜节律紊乱如何影响，目前的知识还存在差距。 米勒细胞功能。因此，本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 修复可纠正穆勒细胞功能障碍。我们提出昼夜节律的假设 心律失常会改变 Kir4.1 表达，导致 Müller 细胞功能障碍。我们建议 以下特定目标来检验我们的假设。目标 1：确定机制 时钟功能障碍与穆勒细胞功能障碍有关。目标 2：评估昼夜节律是否 节律破坏使穆勒细胞对胰岛素信号产生抵抗。目标 3：测试是否修正 db/db 小鼠的中央时钟恢复了穆勒细胞功能障碍。这项研究的结果将 通过研究昼夜节律紊乱的参与来确定 DR 的新发病机制 穆勒细胞功能障碍的节律。昼夜节律的调节可能代表一种新颖的 DR 管理的治疗策略。

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.