The goal of this proposal, which responds in full to NIH PA-09-204 Development and Validation of Disease Biomarkers , is to validate glycated CD59 (the glucose inactivated form of the complement regulatory protein CD59) in human urine, as 1) a biomarker of diabetic complications, 2) a pathogenically relevant indicator of the glycemic load, and 3) a screening tool for Impaired Glucose Tolerance. This proposal is highly translational and addresses major Public Health priorities because 1) 60% of the ≈ 16 million Americans with diabetes will develop complications, which are the leading cause of renal transplants, blindness and amputations in adults, dramatically increase the incidence of heart attacks, and stroke, consuming a staggering 15% of the total U.S. healthcare budget. HbA1c, the clinical gold standard for management of diabetes, does not identify individuals at high risk of developing some complications (e.g. nephropathy) and is not sensitive enough to discriminate individuals with IGT. Chronic hyperglycemia is responsible for the complications of human diabetes but the cellular/molecular mechanism(s) by which hyperglycemia causes tissue damage are poorly understood. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement and the pathogenesis of the complications of diabetes, and 3) developed reagents that allow quantification of glycated hCD59 in human fluids and tissues. Specifically, we have demonstrated that 1) glycated CD59 is present in target organs of diabetic complications, 2) urine glycated CD59 (UglyCD59) can be readily measured in normal urine, and is significantly increased (3-4 fold) in the urine of diabetic subjects. All reagents needed for the validation studies proposed in this application are available, including monoclonal antibodies specific for glycated CD59, assay calibrators, and an archive of well-characterized frozen urine samples from diabetic individuals. To validate UglyCD59 as biomarker for diabetes and its complications we propose to assess: 1) the correlation between UglyCD59 and HbA1c, the dynamics of its changes in relation to the average glucose levels within an individual, and its ability to discriminate ethnic populations at higher risk of vascular complications, 2) UglyCD59 as a marker of impaired glucose tolerance (IGT), and 3) UglyCD59 as a preclinical biomarker to identify diabetic patients at risk of developing complications focusing specifically on diabetic nephropathy (3a) and early small-fiber polyneuropathy (3b). Successful accomplishment of these aims would represent a major advancement in diagnosis, treatment and prevention of the complications of glucose dysmetabolism and diabetes, and should help lower the extremely high costs derived from diabetes and its complications.
The major goal of this proposal is to validate measurements of glycated CD59 (the glucose inactivated form of the key complement regulatory protein known as CD59) in human urine, as 1) a biomarker and predictor of vascular diabetic complications, 2) a pathogenically relevant indicator of the glycemic load, and 3) a screening tool for Impaired Glucose Tolerance (IGT). As a result of this work we hope that glycated CD59 will emerge as a much-needed validated biomarker to a) identify the population at risk of developing the devastating vascular complications of diabetes, b) manage better and perhaps prevent the morbid and life-threatening complications of diabetes, and c) screen the population for IGT. This studies proposed in this project address major Public Health priorities whose relevance is highlighted by the following facts 1) Diabetes and its complications are a leading cause of morbidity and mortality in the adult population, 2) ischemic heart disease, stroke, and peripheral vascular disease account for more than 50% of the mortality rate in the diabetic population, 3) treatment of diabetic cardiovascular disease accounts for ≈1 out of every 10 dollars of the overall US health budget.
|Ghosh, Pamela; Luque-Fernandez, Miguel A; Vaidya, Anand et al. (2017) Plasma Glycated CD59, a Novel Biomarker for Detection of Pregnancy-Induced Glucose Intolerance. Diabetes Care 40:981-984|
|Ghosh, Pamela; Sahoo, Rupam; Vaidya, Anand et al. (2015) Role of complement and complement regulatory proteins in the complications of diabetes. Endocr Rev 36:272-88|
|Ghosh, Pamela; Vaidya, Anand; Sahoo, Rupam et al. (2014) Glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans. J Clin Endocrinol Metab 99:E999-E1006|
|Ghosh, Pamela; Sahoo, Rupam; Vaidya, Anand et al. (2013) A specific and sensitive assay for blood levels of glycated CD59: a novel biomarker for diabetes. Am J Hematol 88:670-6|