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Targeting Notch3 in Lung Cancer

靶向肺癌中的 Notch3

基本信息

批准号：
8231543
负责人：
Thao P. Dang
金额：
$ 21.43万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231543
关键词：
Acute leukemia Adult Apoptosis Biochemical Cancer Model Cancer cell line Cells Cessation of life Clara cell Clinic Complex Data Development Disease Distant Metastasis Dominant Negative Receptor Doxycycline Epithelial Cells Epithelium Family Genes Genetic Transcription Growth Growth Factor Human Implant In Vitro Induction of Apoptosis Intervention Kaposi Sarcoma Ligands Link Lung Lung Neoplasms MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mus Mutation Neoplasm Metastasis Neoplastic Cell Transformation Neuroblastoma Normal Cell Notch Signaling Pathway Nude Mice Oncogenic Organism Pathogenesis Pathway interactions Phenotype Play Process Proteolytic Processing Research Research Personnel Resected Role Serum Signal Pathway Signal Transduction Small Interfering RNA Testing Therapeutic Intervention Tissues Trans-Activators Transgenic Mice Tumor Cell Line Tyrosine Kinase Inhibitor Whole Organism Work base carcinogenesis defined contribution gamma secretase in vivo inhibitor/antagonist insight leukemia lung maturation lung tumorigenesis malignant breast neoplasm member metaplastic cell transformation mortality mouse model neoplastic cell notch protein overexpression presenilin prevent programs promoter protein activation protein complex receptor respiratory secretase trait tumor tumor growth tumor progression tumor xenograft tumorigenesis

项目摘要

Genes that are crucial in the normal development of multi-cellular organisms often play a role in oncogenesis when aberrantly expressed in adult tissues. The Notch signaling pathway is crucial in the cell fate determination, and there is strong evidence demonstrating a role for Notch dysregulation in tumor development. Despite the increasing role of Notch pathway in human cancers, very little was known about the role of NotchS in lung cancers. Our group was the first to link Notch3 pathway with lung cancers. We demonstrated that about 40% of resected lung tumors overexpresses NotchS. In the developing lung, constitutively activated NotchS prevents maturation of lung epithelium. Furthermore, inhibiting the NotchS reduces tumor phenotype, induces apoptosis and renders the tumor cells more dependent of exogenous growth factors. Finally, pharmacologic inhibition of Notch activation reduces proliferation of lung cancer in vitro. Based on our preliminary data, we hypothesize that the NotchS signaling pathway plays a role in the pathogenesis of lung cancer and represents a potential target for intervention. To test these hypotheses, (1) we will examine whether NotchS is sufficient for cellular transformation in vivo using an inducible, Clara cell-driven NotchS expressing mouse model. (2) While transformation is an important aspect in cancer pathogenesis, understanding whether NotchS is important in progression is also important. We will examine the effect of inhibiting NotchS on tumor survival, progression and metastasis in established tumor using an orthotopic lung cancer model. (3) Gamma-secretase is a presenillin-containing protein complex necessary for proteolytic cleavage and activation of Notch receptors. In this aim,we propose to examine the phenotypic and biochemical effects of y-secretase inhibitors on tumor xenografts and to determine the degree to which the anti-tumor effect is Notch-related. These proposed studies will potentially identify NotchS as a target for intervention and provide insights into the mechanism of NotchS-related lung cancer pathogenesis.

基因在多细胞生物的正常发育中起着至关重要的作用