The long range goals of the Program Project are to elucidate and characterize basic mechanisms and pathways of growth related genes as they are normally expressed or inappropriately regulated in neoplastic transformation. Cancer is characterized by unregulated growth of cells which phenotypically fail to recapitulate normal differentiation and development. This project plans to analyze the abnormal regulation of the cancer cell through analyses of different but highly related pathways, beginning with growth factor genes through genes of receptors, extending to growth related genes activating transcription and developmentally regulated genes. Sequences mediating tissue and developmental stage specificity will be identified and used to modify lineage and temporal specific expression of oncogenes and other growth related genes through introduction into cells and transgenic mice. Ultimately, it is hoped to test the hypothesis that understanding of these normal and abnormal regulatory mechanisms will lead to logical approaches for treating neoplastic disease in man. Our shorter term research goals will focus on a growth factor (PDGF A-chain) gene overexpressed in several neoplastic cell lines; on the Bcl-2 gene, the putative oncogene of the t (14:18) human lymphoma: on the nerve growth factor (NGF) receptor gene in developmentally blocked, primary human neuroblastomas; on the NGF induced transcriptional regulatory genes NGFI-A, NGFI-B, and c-fos; and on the cathepsin G gene, a developmental marker of myelomonocytic cells. The work will involve molecular biology, cell biology, biochemistry, and immunology. cDNA and genomic cloning, DNA sequencing and identification of cis-acting gene flanking elements, identification and purification of trans-acting transcriptional proteins, in situ hybridization and immunoperoxidase analyses of tissue mRNA and protein expression respectively transcriptional analyses, and reconstitution experiments in transfected cells and in transgenic mice will be used. Common themes of research interest, research technologies, and reagents exist among these highly interactive investigators. Core Programs are planned in essential expertise and technologies coupled with an interactive program of weekly meetings devoted to discussions of ongoing laboratory progress, generation of new ideas, and journal review. These plus outside speakers, regular investigator programmatic reviews, and external and internal review groups will advance the research goals well beyond those achievable without the context of a program project.
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