# Circadian Rhythms in Müller Cell Dysfunction

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $381,937

## Abstract

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.

## Key facts

- **NIH application ID:** 10186751
- **Project number:** 5R01EY027779-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Ashay D Bhatwadekar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,937
- **Award type:** 5
- **Project period:** 2017-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186751

## Citation

> US National Institutes of Health, RePORTER application 10186751, Circadian Rhythms in Müller Cell Dysfunction (5R01EY027779-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10186751. Licensed CC0.

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