Wound healing defects in the diabetic are a major cause of morbidity and mortality. One of the contributing factors is poor circulation and reduced formation of new capillaries after tissue injury. While arterial insufficiency may be correctable by surgery, medical approaches are required to stimulate formation of new blood vessels (angiogenesis). Thus, several of the known angiogenic growth factors such as FGF, angiopoietin-1, and VEGF have been taken through preclinical and even clinical development as agents to promote neovascularization in a variety of tissues. Only limited, preclinical success has been achieved in the wound healing applications. As part of a functional genomic search of new genes involved in wound healing, it was discovered that cardiac ankyrin repeat protein (CARP), a nuclear factor heretofore only associated with cardiovascular development and cardiac hypertrophy, was sharply induced in early wound healing, and high expression was maintained throughout the phase of granulation tissue formation. To determine the role and potential of this molecule at the wound site, this intracellular protein was expressed in a variety of wound models by both gene gun delivery of plasmid cDNA and by adenoviral delivery. Dramatic increases in neovascularization were immediately evident, suggesting that CARP overexpression either induces the activity of known angiogenic factors, or it acts in a common, downstream pathway that stimulates such processes as endothelial growth, migration, and recruitment. In addition, there may be effects on vascular smooth muscle cells or pericytes that support and stabilize neovascularization. To address these observations, this project will seek a series of interrelated objectives: (1) determine whether and at what dose adenoviral CARP expression leads to improved cutaneous wound healing in normal and diabetic model systems; (2) learn how CARP expression alters the physiology of the vascular endothelial cell and the vascular smooth muscle cell; (3) identify the endogenous sources of CARP at the wound site and test whether CARP is in a pathway downstream of growth factor signaling; (4) test the hypothesis that CARP itself is responsible for the induction of angiogenic factors and if it works by enhancing recruitment of endothelial progenitor cells; (5) utilize microarray analysis to determine which genes are activated by CARP in wounds and in the mesenchymal cells of granulation tissue. This line of investigation is significant because it identifies a novel strategy for improving wound healing in a critical medical area. It is unique since the gene therapy approach has permitted the discovery of a new type of angiogenic agent with the potential to reveal new mechanisms of action. It is challenging because much needs to be learned about how CARP works and whether it can be used as part of an improved therapy for chronic wound repair in the diabetic patient.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065656-03
Application #
6932025
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2003-09-30
Project End
2007-03-31
Budget Start
2005-09-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$232,161
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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