Awardees 2008

PI:Demitrios Vavvas, M.D.
Abstract:Diabetic retinopathy is a major cause of blindness. Its exact pathophysiology is still unclear.  My laboratory’s long term goal is to elucidate the regulatory mechanisms controlling disease pahthophysiology as a prerequisite to the development of novel and better therapies.  The specific hypothesis behind the proposed research is that AMP dependent kinase (AMPK) is a major regulatory factor controlling progression of diabetic retinopathy.  I am basing this hypothesis on a) the observation that Vascular Endothelial Growth factor (VEGF) has been implicated in diabetic retinopathy progression, b) that AMPK has been shown to be upstream of VEGF in other disease models, and c) that intraocular pharmacologic activation of AMPK leads to vasculopathy.  Based on these observations, the experimental focus of this proposal is on the role of AMPK in diabetic retinopathy.  The specific aims are to:

1.  Define the effects of diabetes mellitus on the expression and activity of different AMPK isoforms in the retina of mice.  I will induce diabetes by streptozotocin and high galactose diet and at various time points after disease initiation I will examine activity of the enzyme by immunoprecipitation and protein levels and localization of AMPK isoforms by Western blots and immunocytochemistry.

2.   Examine the effects of AMPK knockout on diabetic retinopathy progression.  Wild type and AMPK isoform specific knockout mice will be rendered diabetic and diabetic retinopathy progression will be assessed at different time points by examining blood retinal barrier breakdown, white blood cell adhesion and levels of previously established pathologic factors in diabetic retinopathy such as VEGF. 

This proposal is so designed that it can examine both a positive and a negative role of AMPK on diabetic retinopathy progression.

PI:Masao Kineki, M.D., Ph.D.
Abstract:Attenuated insulin secretion and impaired compensatory expansion of pancreatic β-cell
mass are major contributors to hyperglycemia in type 2 diabetes. Nitric oxide (NO) and
inducible NO synthase (iNOS) have been implicated in β-cell dysfunction in diabetes.
Nonetheless, limited knowledge is available about the underlying molecular
pathogenesis. Recently, protein S-nitrosylation, a covalent attachment of NO to cysteine
thiols, has emerged as a major mediator of diverse actions of NO. The preliminary data
showed that: (1) deficiency of S-nitrosoglutathione reductase (GSNOR), a negative
regulator of S-nitrosylation, resulted in hyperglycemia with attenuated insulin secretion
on normal chow, and aggravation of high-fat diet-induced hyperglycemia and β-cell
compensation failure compared with wild-type mice; (2) iNOS inhibitor ameliorated
hyperglycemia with increased plasma insulin level in diabetic db/db-BKS mice; and (3)
GSNOR knockdown decreased glucose-stimulated insulin secretion in cultured β-cells.
Based on previous studies and the solid preliminary data, we wish to test the hypothesis
that GSNOR plays important roles in insulin secretion and protection from obesityinduced β-cell damage. Aim 1 will test the hypothesis that GSNOR deficiency impairs insulin secretion in mice. Aim 2 will determine whether increased expression of GSNOR protects from obesity-induced diabetes in β-cell-specific GSNOR transgenic mice. Aim 3 will determine whether GSNOR deficiency aggravates obesity-induced β-cell damage. This project will identify GSNOR as a novel potential molecular target to prevent and/or reverse β-cell dysfunction in obesity-related diabetes. The proposed studies will provide novel mechanistic insights into β-cell dysfunction to help develop novel preventive and/or therapeutic interventions against type 2 diabetes.

PI:Paolo Fiorina, M.D.
Abstract:Diabetic nephropathy is the most serious and important complication faced by diabetic patients. Despite much progress and an overall improvement in the treatment of diabetic nephropathy, the development of chronic renal failure is almost inevitable. In the United States, there are presently 20 million diabetic patients and diabetes is rapidly becoming the leading cause of end-stage renal disease. The common denominator in a variety of kidney diseases, such as diabetes mellitus, is glomerular dysfunction (nephrotic syndrome) involving a massive loss of protein in the urine (proteinuria) due to podocyte dysfunction. Glomerular podocytes are the final barrier to urinary protein loss, and every nephrotic syndrome is characterized by abnormalities in podocyte function. The integrity of the podocyte membrane is essential to the retention of protein during the filtration process. In diabetes, podocytopenia is evident, and podocytes are found in the urine of diabetic patients. B7.1 or CD80 is a transmembrane protein normally expressed on antigen-presenting cells (APCs) that has a role in many immunological processes, including the progression of chronic allograft nephropathy. Interestingly, the appearance of proteinuria requires B7 induction in the kidney, as it was demonstrated to be abrogated in B7.1 KO mice. The role of B7.1 in diabetic nephropathy is unknown. The need for new therapies in this field makes the exploration of the role of this molecule in diabetic nephropathy imperative. We propose that B7.1 can have a role in diabetic nephropathy and that by blocking B7.1 with CTLA4-Ig (Y100F) we can abrogate the progression of this disease. The potential translational approach is the major strength of this proposal. B7.1 blockers are available for human use and appear to be safe. CTLA4-Ig, the B7.1 blocker we proposed to use, has been evaluated in humans for psoriasis and arthritis, with very few adverse effects and no increase in infection or neoplasia. If confirmed our data will serve as a basis for a new treatment of diabetic nephropathy


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