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Abstract
Grant Number: 1R01CA112405-01 Project Title: A Molecular Basis for Neuroendocrine Carcinogenesis
PI Information: Name Title GRIMES, H LEIGHTON. lee.grimes@cchmc.org ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): The cloning of oncogenes and tumor suppressor genes over the last twenty years has allowed profound insight into the molecular basis of cancer, and subsequently provided molecular targets for clinical intervention. However, the molecular basis of neuroendocrine lung tumors such as small cell lung carcinoma (SCLC) is still not understood. We hypothesize that the Growth factor independence-1 (GFI1) transcriptional repressor oncoprotein and the basic helix-loop-helix (bHLH) transcription factor human achaete and scute homolog- 1 (ASH1) are modifiers of SCLC because they control neuroendocrine differentiation of lung epithelium. Striking parallels can be drawn between the activity of Drosophila orthologs of GFI 1 and ASH 1 in fly neurogenesis, and the development of pulmonary neuroendocrine cells and SCLC. Using conditional knockout and transgenic mouse models, we will determine the requirement for GFI1 and ASH1 in SCLC oncogenesis, acute lung airway injury repair and pulmonary neuroendocrine cell development. Finally, a molecular dissection of GFI1 target gene regulation will link transcription effects to lung phenotypes. The proposed experiments should critically determine how key participants in a newly discovered Drosophila developmental cascade are relevant to the induction of SCLC in vivo.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
genetic regulation, neoplasm /cancer genetics, neuroendocrine system, oncoprotein, small cell lung cancer
cell differentiation, growth factor, hormone related neoplasm /cancer, oncogene, phenotype, protein structure, respiratory epithelium, transcription factor
genetically modified animal, histology, immunocytochemistry, in situ hybridization, laboratory mouse, polymerase chain reaction
Institution: UNIVERSITY OF LOUISVILLE OFFICE OF GRANTS MANAGEMENT LOUISVILLE, KY 40292 Fiscal Year: 2005 Department: SURGERY Project Start: 01-FEB-2005 Project End: 30-SEP-2005 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1