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 Mller 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. Mller cells regulate K+ balance via inwardly rectifying Kir4.1 channels. In DR, the Mller 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 Mller 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 Mller cell dysfunction. We propose the hypothesis that circadian arrhythmia will alter Kir4.1 expression leading to a Mller 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 Mller cell dysfunction.
Aim 2 : To assess whether circadian rhythm disruption renders Mller cells resistant to the insulin signal.
Aim 3 : To test if correction of central clock in db/db mice restores the Mller cell dysfunction. The outcome of this study will ascertain a novel pathogenic mechanism of DR by studying the involvement of disturbed circadian rhythms in Mller cell dysfunction. Modulation of circadian rhythms may represent a novel treatment strategy for the management of DR.

Public Health Relevance

Mller cells are dysfunctional in diabetic retinopathy (DR) due to downregulation of Kir4.1 channels. Circadian rhythm disruption leads to type 2 diabetes and DR. We propose that circadian rhythm disruption will lead to a decrease in Kir4.1 activity and Mller cell dysfunction.

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National Eye Institute (NEI)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Greenwell, Thomas
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Indiana University-Purdue University at Indianapolis
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Beli, Eleni; Yan, Yuanqing; Moldovan, Leni et al. (2018) Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice. Diabetes 67:1867-1879
Thompson, Kayla; Chen, Jonathan; Luo, Qianyi et al. (2018) Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells. PLoS One 13:e0193280