Experimental approaches to improve our understanding and treatment of major diabetic complications have focused on single mechanisms or pathways and resulted in the identification of specific mechanisms that drive diabetic damage. With the recent emergence of genome-wide profiling capatiilities and comprehensive data integration strategies, biomedical research is at a point where it can move toward a more holistic view of tissue responses to complex chronic diseases. This is of particular relevance to diabetic end-organ damage since multiple mechanisms converge to slowly alter the cellular milieu in target tissues in diabetes, mandating the integration of separate pathways to elucidate the complex pattern of responses in the treatment or prevention of diabetic complications. Indeed, therapies that have worked best to prevent progression of diabetic nephropathy (DN) and polyneuropathy (DPN) affect multiple pathways and mechanisms, whereas those that target a single, """"""""critical"""""""" pathway have often yielded disappointing results. Our team of scientists will use a systems biology approach to achieve 3 goals, to: 1) efficiently identify the essential cellular responses that lead to DN and DPN, 2) identify those responses that are most amenable to conventional and novel therapies, and 3) discover biomarkers for the critical cellular alterations that lead to complications and respond to effective therapies. Our strategy relies on information-rich sequential and reciprocal transcriptomic, protein and metabolite comparisons between humans with DN and DPN and the best extant murine models of these complications. Our hypothesis is that a complex network of responses, including but not limited to those altered by oxidant stress, leads to the onset and progression of diabetic microvascular complications. These critical responses will be identified by performing genome-wide RNA and metabolite profiles from kidney and nerve of humans with DN and DPN. The expression data sets of human end-organ damage from untreated and treated animals will be compared to data sets obtained from kidney and nerve from murine models with DN and DPN. Three different treatment paradigms known to ameliorate DN and DPN will be used as independent tools in the mouse models to identify new critical responses that lead to complications and are responsible for effective treatment in humans. This reciprocal cross-species approach will identify candidate pathways and molecules whose regulation alters disease progression. Finally, we will return to the murine models of DN and DPN to discover new biomarkers that will be useful in the diagnosis and therapeutic management of human DN and DPN.

Public Health Relevance

Two of the most devastating complications of diabetes are kidney disease and nerve disease which both result in increased illness and death. The multifactorial causes of these complications remain poorly understood and treatments are limited. Therefore, we have devised a team approach to use """"""""systems biology"""""""" to study diabetic humans with these complications, with the help of mouse models, and to identify the critical molecular responses that cause kidney and nerve damage and that can be reversed by therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK082841-05
Application #
8448319
Study Section
Special Emphasis Panel (ZDK1-GRB-W (O4))
Program Officer
Jones, Teresa L Z
Project Start
2008-09-30
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,117,286
Indirect Cost
$392,460
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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