Alan Attie

Personal Information
Title Professor
Expertise All Complications
Institution University of Wisconsin-Madison
Data Summary
Grants/SubContracts 2
Progress Reports 2
Publications 3
Protocols 0
Committees 1


Causal genes and gene networks for diabetic nephropathy
Diabetic nephropathy is the leading cause of end-stage renal disease. We have developed a model of type 2 diabetes that has turned out to be an excellent model of human diabetic nephropathy. We have mapped diabetes and diabetes-related traits in 495 mice from an F2 intercross between our mouse strain and a strain that is diabetes-resistant. In addition, we have obtained kidneys from these mice; one kidney was subjected to microarray analysis and the other to quantitative histological analysis of nephropathy. The histological analysis is being done collaboratively with Dr. Jeffrey Hodgin (University of Michigan). The objectives of this pilot study are: 1. Carry out quantitative trait locus (QTL) mapping of diabetic nephropathy phenotypes in an F2 sample derived from obese C57BL/6 and BTBR mice. Integrate the disease QTLs with expression QTLs to develop causal network models underlying the disease. 2. Derive congenic mouse strains that isolate specific loci and enable positional cloning of individual diabetic nephropathy genes. The congenic strains will be new models for individual components of diabetic nephropathy. Our F2 intercross segregates key features of human diabetic nephropathy. Our work will deliver individual causal genes for the disease. Perhaps more importantly, we will develop causal network models that include intermediate traits leading to diabetic nephropathy. Causal genes and intermediate traits are a potential source of new therapeutic targets. In summary, this project will deliver QTLs for diabetic nephropathy, new congenic animal models exhibiting individual features of the disease, and causal network models providing mechanistic information, and potentially new therapeutic targets for the disease. Our goal is to use this preliminary data to obtain an R01 grant a year from now.

Treatment of Diabetic Nephropathy through Modulation of Lipoprotein Metabolism
Genetic and environmental factors contribute to the risk of diabetic nephropathy (DN) among people with diabetes. Inflammation is a key feature of DN. Inflammation is likewise a key feature of atherosclerosis. Hyperlipidemia plays a key causal role in atherosclerosis and its relationship to the inflammatory processes is quite well-studied. However, the role of hyperlipidemia in DN is less well explored. However, there is evidence linking hypertriglyceridemia with DN. A mechanism that links hyperlipidemia with atherosclerosis is the production of adducts between proteins and oxidized lipids. These adducts are epitopes that are recognized by the innate and adaptive immune responses and initiate an inflammatory process. We present evidence that oxidation epitopes present in human atherosclerosis are also present in DN. Thus, the premise of this proposal is that there is a common etiology between the inflammatory processes that underlie atherosclerosis and diabetic nephropathy. Ionis, Inc. has developed antisense oligonucleotides (ASOs) against apoC3, for the treatment of hypertriglyceridemia. Reducing apoC3 levels increases lipoprotein lipase-mediated removal of triglycerides from the bloodstream, primarily in adipose tissue. The anti-apoC3 ASOs are safe and effective, and currently in use in the clinic. The two principal investigators of this P&F proposal, Alan Attie and Charles Alpers, identified the BTBR-ob/ob mouse as an excellent model of human DN. The objective of this P&F project is to test the hypothesis that targeted ASO therapy for the dyslipidemia characteristic both of the BTBR-ob/ob mouse and humans with T2D will prevent the development of DN. The project will develop a treatment protocol using Ionis ASOs to normalize triglycerides in BTBR-ob/ob mice. Animals will then be treated and their nephropathy analyzed by measurement of urinary albumin, total protein, and urea. Kidneys will be analyzed histologically and by electron microscopy. The kidneys will be probed for the expression of lipid oxidation protein epitopes similar to those seen in atherosclerotic lesions. The studies will determine whether diversion of plasma lipids to adipose tissue will spare kidneys of nephropathy in the setting of type 2 diabetes.

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