? In humans with diabetes, abnormal angiogenesis contributes to the development of end-organ damage. In this regard, """"""""excessive"""""""" angiogenesis and increased activity of the vascular endothelial growth factor (VEGF) signaling pathway have been associated with diabetic complications such as retinopathy. In contrast, an inadequate angiogenesis response with a reduced capacity to promote collateral blood vessel growth in cardiac and particularly peripheral skeletal muscle result in more severe manifestations of vascular disease in diabetes. However, the mechanisms responsible for the loss of control of angiogenesis in diabetes and how this dysregulation modulates tissue pathology are not clear. We hypothesize that abnormal signaling in VEGF-associated pathways is a critical factor in the pathogenesis of diabetic complications including peripheral artery disease (PAD) and nephropathy. Furthermore, we posit that distinct properties of individual tissues determine the effects of diabetes on the local angiogenesis response, shaping the resulting pathology. Accordingly, to develop better models of diabetic PAD and nephropathy, we will generate mouse lines with inducible alterations of angiogenic signaling pathways targeted to specific cell lineages in blood vessels, skeletal muscle and kidney. Because both enhanced and diminished VEGF activities have independently been associated with diabetic complications, we will produce models with up- or down-regulated angiogenic signaling. The long-term goals of our studies are: (1) To understand how alterations in angiogenic factors contribute to the development of diabetic complications and (2) To develop mouse models of diabetic PAD and nephropathy that more faithfully reproduce the respective human conditions. To achieve these goals we propose the following specific aims: 1. To develop mouse models with genetic modifications of key signaling pathways linked to angiogenesis. 2. To determine the effects of diabetes on angiogenic signaling in a well-established model of peripheral artery disease. 3. To define the consequences of altered angiogenic signaling on the development of albuminuria and nephropathy in diabetes. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK076136-02
Application #
7288317
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Ketchum, Christian J
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$291,417
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Dolber, Paul C; Jin, Huixia; Nassar, Rashid et al. (2013) The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice. Neurourol Urodyn :
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Jeansson, Marie; Gawlik, Alexander; Anderson, Gregory et al. (2011) Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest 121:2278-89
Gurley, Susan B; Mach, Carrie L; Stegbauer, Johannes et al. (2010) Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am J Physiol Renal Physiol 298:F788-95
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Hazarika, Surovi; Angelo, Michael; Li, Yongjun et al. (2008) Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia. Arterioscler Thromb Vasc Biol 28:2144-50

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