During the multistep transformation of normal epithelial cells into colorectal cancer (CRC), cells acquire a limited set of essential features that move the cells toward malignancy. Two of these fundamental properties acquired early during the CRC latency period include cell autonomous dysregulation of growth control and the ability to trigger neoangiogenesis to feed tumor growth. Delineating and therapeutically targeting molecular events that underlie the pre-malignancy period could lead to more effective intervention strategies against CRC. Recently, genes that may play key roles in each of these two early events were identified. Cyclin dependent kinase 4 (Cdk4) regulates the re-entry of cells into the G1 phase of the cell cycle. Preliminary work suggests that truncating adenomatous polyposis coli (Ape) gene mutations, a hallmark of CRC initiation, triggers Cdk4 dysregulation in the intestinal stem cell compartment/crypt and that Cdk4 activity plays an important role early in tumorigenesis. Preliminary work also identified a group of tumor endothelial marker (TEM) genes that are selectively expressed on endothelial cells during neoangiogenesis in CRC, but are not expressed on resting endothelial cells. The proposed studies are designed to elucidate the role of Cdk4 and mTem1 in the growth and inhibition of intestinal tumors.
The aims are: 1) To characterize expression of Cdk4 in intestinal stem cell compartments during mucosal epithelial growth, differentiation, and tumor formation, and 2) To characterize the role of mTem1 expression in growing blood vessels and to examine the effects of mTem1knock out on tumor formation, and invasiveness. The research complements the candidate's training which includes a veterinary degree, post doctoral pathology fellowship, and pending PhD degree. The research will be conducted in the laboratory of Dr. David L. Huso, Comparative Medicine with support from Drs. Bert Vogelstein and Kenneth Kinzler, Oncology. In this rich training environment, the award would support the candidate in establishing himself as an independent researcher.
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