Mitochondrial (MT) dysregulation and resultant energy imbalance is associated with various chronic diseases including neuro-degeneration, ischemia/reperfusion, and diabetic complications such as diabetic retinopathy (DR). Recently, we published that pro-oxidant thioredoxin interacting protein (TXNIP) is significantly up-regulated in DR and under hyperglycemia in retinal cells in culture including Muller cells (MC) and mediates cellular oxidative stress and inflammation. TXNIP has recently been implicated by several studies as a critical protein in the pathogenesis of diabetes and its complications including DR. TXNIP binds to thioredoxin (Trx), a redox anti-oxidant protein, inhibiting its reactive oxygen species (ROS) scavenging and thiol reducing capacity; therefore, results in cellular oxidative/nitrosative (ROS/RNS) stress and aberrant protein s-nitrosylation. Furthermore, MC are important for retinal health and activated MC (gliosis) induces aberrant gene expression for cytokines and growth factors to maintain retinal homeostasis. However, prolonged MC activation is injurious in DR. Therefore, our overall hypothesis is that TXNIP is critical for MT dysfunction and MC activation in the development of DR. We propose to test two specific aims:
aim 1. that TXNIP induces MT dysfunction and evokes nuclear stress responses in early DR;
and aim 2. that TXNIP regulates MT fission and mitophagy in early DR. To address the objectives, we will use streptozotocin (STZ)-induced type 1 diabetic models of rat and mouse in conjunction with manipulation of TXNIP expression levels in the retina. In vitro studies using retinal MC will also be performed to dissect the molecular mechanisms as to how TXNIP induces MT dysfunction and mitophagy, which specifically removes damaged MT. Our proposal is innovative because we address still unexplored important areas of research in DR. These include: (i) MT retrograde stress signaling to maintain MT homeostasis in DR; (ii) molecular mechanism(s) of MT fission and mitophagy, critical for preservation of MT homeostasis in DR: (iii) understanding the role played by TXNIP in retinal MC activation (gliosis) and retinal neuronal injury/death in DR; and (iv) development of a novel strategy for TXNIP knock down in the retina by siRNA-targeted to TXNIP promoter and chromatin closing (RNAi eTGS). Hence, our proposed innovative studies will fill the knowledge gap that currently exists in understanding DR initiation and progression. Furthermore, the results will allow us to identify potential targets for developing new gene/drug therapies and ameliorate the ocular complications of diabetes.

Public Health Relevance

Chronic hyperglycemia-associated oxidative stress and low grade inflammation are considered to play a causative role in the pathogenesis of diabetic retinopathy. However, effective drug treatments to prevent diabetic retinopathy are not available at present. It is anticipated that the results of the proposed research will lead to new research paradigms, which are previously unknown, and allow us to develop novel mechanism-based gene therapies to prevent or slow down diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023992-02
Application #
8976841
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2014-12-02
Project End
2019-11-30
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Singh, Lalit P; Devi, Takhellambam S; Yumnamcha, Thangal (2017) The Role of Txnip in Mitophagy Dysregulation and Inflammasome Activation in Diabetic Retinopathy: A New Perspective. JOJ Ophthalmol 4:
Devi, Takhellambam Swornalata; Somayajulu, Mallika; Kowluru, Renu Anjan et al. (2017) TXNIP regulates mitophagy in retinal Müller cells under high-glucose conditions: implications for diabetic retinopathy. Cell Death Dis 8:e2777
Pradhan, Priya; Upadhyay, Nisha; Tiwari, Archana et al. (2016) Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression. New Front Ophthalmol 2:192-204