This application encompasses a 5-year training program designed for the development of a clinician scientist. The principal investigator is an Assistant Professor of Medicine, staff physician of the Cardiology Section of the Department of Medicine at Dartmouth-Hitchcock Medical Center and an investigator at the Angiogenesis Research Center of Dartmouth Medical School. Prior to his current appointment, the principle investigator was involved in developing and characterizing a mouse model of collateral artery growth as a postdoctoral fellow in the laboratory of Dr. Wolfgang Schaper. Dr. Michael Simons, the chief of the Cardiology Section and of the Angiogenesis Research center, will serve as his mentor. Dr. Simons is an internationally recognized leader in the field of angiogenesis research and has trained many junior faculty scientists, postdoctoral fellows and graduate students. An advisory committee of highly recognized medical scientists will provide further scientific and career advice. A better understanding of the mechanisms of compensatory collateral artery growth, or arteriogenesis, is sorely needed. The research plan of this proposal focuses on the functional validation of genes which were found to be differentially regulated in regions of collateral growth in mice;specifically two factors will be studied which were upregulated on mRNA level in preliminary studies, and which may exemplify the importance of pro-and anti-inflammatory mechanisms in collateral artery growth.
Specific Aim I is to define the role of tissue-specific expression of the primarily pro-inflammatory cell adhesion protein osteopontin in collateral artery growth in a mouse femoral artery ligation model.
Specific Aim II is to define the role of the primarily anti-inflammatory cell surface anticoagulant thrombomodulin in arteriogenesis in the same model. Existing knock-out and transgenic mice will be used and mouse lines with regulatable tissue specific promoters will be generated for these studies and the results will advance the knowledge about the biology of collateral artery growth with potentially important therapeutic implications. The Angiogenesis Research Center at Dartmouth Medical School is an ideal setting for the training of clinician-scientists by incorporating the expertise of scientists with diverse backgrounds and by offering outstanding access to state of the art molecular biology and imaging technologies and expertise.