MOLECULAR DETERMINANTS OF ANGIOGENSIS IN ORAL CANCER

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DESCRIPTION: Dr Lingen's proposed career development plan consists of multiple rotations through laboratories with novel expertise which will be directly applicable to his proposed research endeavors. The time frames range from 1 month to 3 months and the locations vary from across the country to within the same institution. During the first year, he has made arrangements to visit Dr. Leroy Hood at the University of Washington for 1 month and learn the cDNA microarray technology. During the second year, he will work within the laboratory of Dr. Brian Nickoloff at Loyola University to gain hands-on experience in the development of both retroviruses and adenoviruses that contain his genes of interest. During year 3, he proposes a 3-month rotation through Dr. Lucio Miele's laboratory at Loyola to gain knowledge of how to identify key transcription factors and perform promoter analyses. In year 4, he visits the laboratory of Dr. Elaine Fuchs at the University of Chicago for a 3-month period to generate transgenic mice in which the expression of the transgenes will be under the control of an inducible endothelial cell specific promoter. The final rotation has not been determined, but will remain available for later consideration of state-of-the-art techniques needed. In addition to the above mentioned rotations, Dr. Lingen also plans to participate and lecture in courses related to research ethics at Loyola University. The described research project is identical to the Dr. Lingen's current R01 grant which has been peer-reviewed and funded. The specific aims are: 1) To characterize in detail the profile of functional retinoic acid receptors expressed in microvascular endothelial cells by performing Northern and Western blots, and by performing electromobility shift assays to determine the functional status of the expressed receptors. 2) To determine which of the expressed retinoic acid receptors are responsible for causing microvascular endothelial cells to become refractory to inducers of angiogenesis by employing receptor selective ligands, and by introducing either dominant negative, wild-type or chimeric retinoic acid receptors into microvascular endothelial cells. 3) To study retinoic acid-mediated inhibition of in vivo angiogenesis by introducing human microvascular endothelial cells containing a retrovirally driven dominant negative, wild-type or chimeric retinoic receptors into mice and observing their incorporation into newly forming vessels.