The incidence of chronic metabolic diseases such as obesity and diabetes has increased dramatically and constitutes one of the major threats to global health. Recent studies have indicated that cell stress response plays an essential role in the pathogenesis of type 2 diabetes (T2D). Oxidative stress and endoplasmic reticulum (ER) stress cooperatively promote cell dysfunction, apoptosis and insulin resistance. While the activators and downstream effects of cell stress have been partially characterized, much is unknown regarding the molecular mechanisms by which the cell stress responses are regulated. Our lab and others have recently characterized the NLR (NBD-LRR) family of proteins, which have been shown to mediate the cell stress response to microbes and environmental stressors. My preliminary data indicates that NLRX1, a mitochondria-localized NLR protein, promotes ER stress response by mediating the generation of mitochondrial reactive oxygen species (mROS). Mechanistically, NLRX1 directly associates with ECSIT (evolutionarily conserved signaling intermediate in Toll pathways) and TRAF6 (TNF receptor-associated factor 6), both of which are important in mitochondrial respiratory chain assembly. NLRX1-deficient (Nlrx1-/-) cells are protected from ER stress-inhibited insulin-PI3K-Akt pathway. Moreover, Nlrx1-/- mice were protected from obesity- induced insulin resistance by high-fat diet (HFD) feeding. Therefore, I hypothesize that NLRX1 mediates mROS generation by facilitating ECSIT-TRAF6 function, which subsequently promotes ER stress, and that the NLRX1-mediated cell stress responses impair insulin signaling in insulin target tissues. I will employ T2D (HFD feeding and leptin-deficient ob/ob mice) animal models to examine the function of NLRX1-mediated cell stress responses in insulin resistance. I will examine how NLRX1 controls ECSIT function and mROS generation. The goal of the proposal is to examine the mechanism of the interaction between NLRX1-mediated oxidative stress and ER stress in promoting cell dysfunction and a defect in insulin signaling. The proposed genetic and biochemical analyses and animal model studies will provide novel insights into the regulation and function of metabolic signaling pathways. Further studies could lead to the identification of new therapeutic targets and ultimately help develop rational, mechanism-based treatment strategies that target obesity and diabetes.

Public Health Relevance

Although cell stress responses, including oxidative stress and ER stress, play detrimental roles in the pathogenesis of obesity and diabetes, how cell stress responses are mediated remains largely unknown. Based on my preliminary data, I plan to study the role and mechanism of NLRX1-mediated cell stress responses in diabetes. Understanding the role of cell stress mediators in the development of obesity and diabetes will be instrumental for the generation of new strategies targeting the prevention and/or treatment of the diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK098307-01
Application #
8487694
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2013-07-01
Project End
2016-05-31
Budget Start
2013-07-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$150,036
Indirect Cost
$11,114
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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