Fliser et al. identified the presence of insulin resistance in non-diabetic patients with IgA or inherited nephropathies and nearly normal values of serum creatinine and GFR, pointing out that this complication is not restricted to dialysis patients. They concluded that chronic kidney disease (CKD) rather than a specific kidney disease causes insulin resistance. However, mechanisms causing insulin resistance in CKD are unsettled: there appears to be normal binding of insulin to its receptor with the defect present in intracellular signaling. My project i based on a novel pathway I uncovered, namely that CKD stimulates the expression of a membrane- bound, tyrosine phosphatase, Signal Regulatory Protein Alpha (SIRP-alpha), resulting in reduced tyrosine phosphorylation of the insulin receptor and its downstream mediator, insulin receptor substrate-1. My goal is to determine how CKD-stimulated SIRP-alpha induces skeletal muscle wasting and cardiac muscle fibrosis and dysfunction. CKD is a major concern for U.S. Veterans because of the increased morbidity and mortality it invariably causes, including insulin resistance. My long-term goal is to identify mechanisms causing insulin resistance in CKD and to develop therapeutic strategies to prevent its catabolic complications. The development of insulin resistance is not limited to CKD but occurs in obesity, type 2 diabetes and inflammatory conditions and it is tempting to speculate that results of my studies might extend to other conditions. Fortunately, the research interests of my mentors, Drs. Garcia and Mitch, are at least in part similar to my goals while Drs. Chan, Justice & Taegtmeyer can help me address experimental problems. My Preliminary Results indicate that increased SIRP-alpha expression occurs via NF-alphaB and that silencing SIRP-alpha in muscle cells enhances insulin signaling and suppresses protein wasting.
Specific Aim 1 : to determine whether tyrosine phosphorylation of SIRP-alpha recruits SHP2 and whether the SIRP-alpha-SHP2 complex reduces tyrosine phosphorylation of the insulin receptor and IRS-1.
Specific Aim 2 : to study the mouse with whole body KO of SIRP-alpha by inducing CKD. My goal is to examine how CKD in the absence of SIRP-alpha affects insulin signaling and muscle metabolism. I will determine how CKD affects muscle metabolism in mice with muscle-specific KO of SIRP-alpha.
Specific Aim 3 : we also find increased SIRP-alpha expression in hearts of mice with CKD. Since diabetes can cause fibrosis in the heart with impaired function, I plan to determine if SIRP-alpha KO mice are protected against the development of CKD-stimulated cardiac fibrosis and decreased function. My short-term goals are to address these Specific Aims as a prelude to becoming an independently- funded principle investigator. My long term goal is to identify mechanisms causing the complications of impaired insulin signaling and CKD. Specifically, I will enhance my knowledge and skills in didactic courses plus seminars (e.g. cell and molecular biology, grant and manuscript writing, ethics in biomedical research and translational research design). I believe I have the necessary environment to grow into a successful investigator, including strong mentorship, a world-renowned Career Advisory Committee and participation in local and national research meetings. To extend my research, I am applying for the VA-CDA and hope to develop therapies to improve the quality of life of U.S. Veterans, suffering from conditions such as CKD, type 2 diabetes or obesity that are characterized by impaired insulin signaling.

Public Health Relevance

The United States Renal Data System (USRDS) estimates that chronic kidney disease (CKD) affects 1 in 10 Americans, contributing to their morbidity. A frequent, major complication of CKD is the initiation of insulin resistance because it stimulates loss of muscle mass and can contribute to the development of heart disease. My goal is to identify how CKD causes insulin resistance which in turn, stimulates the complications of CKD so that strategies can be developed to improve intracellular defects in insulin signaling.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
1IK2BX002492-01A1
Application #
8821393
Study Section
Endocriniology A (ENDA)
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Michael E Debakey VA Medical Center
Department
Type
DUNS #
078446044
City
Houston
State
TX
Country
United States
Zip Code
77030
Sun, Lijing; Si, Meijun; Liu, Xinyan et al. (2018) Long-noncoding RNA Atrolnc-1 promotes muscle wasting in mice with chronic kidney disease. J Cachexia Sarcopenia Muscle 9:962-974
Dave, Natasha; Wu, Jiao; Thomas, Sandhya (2018) Chronic Kidney Disease-Induced Insulin Resistance: Current State of the Field. Curr Diab Rep 18:44
Awan, Ahmed A; Thomas, Sandhya S; Erickson, Kevin F (2018) Making Policy in the Dark: The Use of Activated Vitamin D Under Bundled Payments for Dialysis Care. Am J Kidney Dis 72:161-163
Thomas, Sandhya S; Mitch, William E (2017) Parathyroid hormone stimulates adipose tissue browning: a pathway to muscle wasting. Curr Opin Clin Nutr Metab Care 20:153-157
Yu, Rizhen; Chen, Ji-An; Xu, Jing et al. (2017) Suppression of muscle wasting by the plant-derived compound ursolic acid in a model of chronic kidney disease. J Cachexia Sarcopenia Muscle 8:327-341
Liu, Xinyan; Yu, Rizhen; Sun, Lijing et al. (2017) The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease. Kidney Int 92:336-348
Thomas, Sandhya S; Zhang, Liping; Mitch, William E (2015) Molecular mechanisms of insulin resistance in chronic kidney disease. Kidney Int 88:1233-1239