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Menin/MLL promotes cell survival in the setting of EGFR inhibition

Menin/MLL 在 EGFR 抑制的情况下促进细胞存活

基本信息

批准号：
9114616
负责人：
Bryson William Katona
金额：
$ 15.55万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-22 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114616
关键词：
Academic Medical Centers Achievement Advisory Committees Apoptosis Autophagocytosis Award Azoxymethane Benign Binding Cell Survival Cells Colitis Colon Carcinoma Colorectal Complex Data Development Disease Doxycycline Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Epithelial Epithelium Gastrointestinal Diseases Gene Expression Genes Genetic Transcription Goals HCT-15 HT29 Cells Health Histone H3 Homeobox Genes Homeostasis Human In Vitro Inflammatory Bowel Diseases Laboratories Lead Literature Lysine MAP Kinase Gene MEN1 gene Malignant - descriptor Mediating Menin Mentorship Methods Mixed-Lineage Leukemia Modification Molecular Mus Nuclear Matrix-Associated Proteins Nuclear Protein Pathogenesis Pathway interactions Physicians Play Receptor Inhibition Receptor Signaling Regulation Reporting Research Research Proposals Role Scientist Signal Pathway Signal Transduction Sodium Dextran Sulfate Testing Therapeutic Tumor Suppression Xenograft procedure base beta catenin cancer cell carcinogenesis career cell growth colitis associated cancer direct application epigenetic regulation histone methyltransferase improved in vivo injury and repair innovation knock-down leukemia mouse model novel novel therapeutics research study response small hairpin RNA villin

项目摘要

DESCRIPTION (provided by applicant): Signaling through the epidermal growth factor receptor (EGFR) is important in colonic epithelial homeostasis and disease. Therefore, finding new methods to modulate EGFR signaling could have significant therapeutic application toward the treatment of gastrointestinal diseases. Targeted epigenetic modulation represents a novel method to regulate cell responses to EGFR signaling. Preliminary data from our lab including an unbiased epigenetic shRNA screen, demonstrated that the nuclear scaffold protein menin and its histone methyltransferase binding partner mixed lineage leukemia (MLL) are critical for cell survival in the setting of EGFR inhibition. There is no known connection between menin/MLL and EGFR signaling reported in the literature, leading us to our hypothesis that the menin/MLL axis serves as an important epigenetic mechanism that enables colonic epithelial-derived cells including colon cancer cells to survive when EGFR signaling is inhibited. This hypothesis will be pursued in two interrelated Specific Aims: (1) Define the mechanism of menin/MLL mediated cell survival in the setting of EGFR inhibition. (2) Determine if menin/MLL is important for cell survival during EGFR inhibition in vivo. This proposal will utilize both in vitro and in vivo approaches to define the crosstalk between the menin/MLL and EGFR signaling pathways that is crucial for menin/MLL mediated cell survival in the setting of EGFR inhibition. The experiments in this innovative proposal will also have direct application toward the development of novel therapies for the treatment of both benign and malignant colorectal diseases, including inflammatory bowel disease and colon cancer. In addition, this research proposal will be supported in an integrated manner through exceptional mentorship, an already constituted research advisory committee, and unequivocal divisional and institutional commitment. Finally, this K08 award will serve as a basis for the ultimate achievement of my career goal to become an independent physician-scientist at a major academic medical center.