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。大约有700万美国人 患有这种威胁视力的糖尿病并发症。病原学的复杂性 糖尿病视网膜病变的机制是缺乏治疗穆勒博士的有效治疗方法的主要原因 细胞是视网膜的主要胶质细胞，由于其独特的特性，在DR的发病机制中起着至关重要的作用。 横跨整个视网膜的解剖位置和特殊功能，如水和钾 平衡、神经递质的摄取和糖原储存。米勒细胞通过调节钾平衡 向内整顿KIR4.1通道。在DR中，Müler细胞功能障碍和肿胀是由于 Kir4.1通道的下调和水分的积累。昼夜节律起着一种 在调节身体的许多生化和生理功能方面起着重要作用。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 T2D大鼠，我们报告了一种节律调节时钟基因的功能障碍模式在Dr.We进一步 使用关键的时钟重置基因PER2测试时钟在DR中的重要性，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在视网膜表现出昼夜节律，Kir4.1的这种生物节律是 (Ii)Kncj10(Kir4.1的基因)受时钟基因调控；以及(Iii) 胰岛素受体底物1(IRS-1)介导的胰岛素信号对Kir4.1的表达至关重要。 然而，关于被扰乱的昼夜节律如何影响，还存在一个知识空白。 Müler细胞功能。因此，本研究的目的是了解昼夜节律的作用。 Kir4.1功能调控机制及昼夜节律评价 修复可以纠正Müler细胞功能障碍。我们提出的假设是昼夜节律 心律失常会改变Kir4.1的表达，导致Müler细胞功能障碍。我们建议 以下是检验我们假设的具体目的。目标1：确定 生物钟功能障碍与Müler细胞功能障碍有关。目标2：评估昼夜节律 节律紊乱使Müler细胞对胰岛素信号产生抵抗。目标3：测试是否正确 Db/db小鼠的中枢时钟可恢复Müler细胞功能障碍。这项研究的结果将 通过研究昼夜节律紊乱确定DR的一种新的发病机制 米勒细胞功能障碍的节律。昼夜节律的调制可能代表了一种新的 管理DR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.