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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112405-04
Application #
7340709
Study Section
Special Emphasis Panel (ZRG1-CG (01))
Program Officer
Mietz, Judy
Project Start
2005-02-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$233,253
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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