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：
8949911
负责人：
Bryson William Katona
金额：
$ 15.7万
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/8949911
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 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 public health relevance 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.

描述（由应用提供）：通过表皮生长因子受体（EGFR）发出信号在结肠上皮稳态和疾病中很重要。因此，找到调节EGFR信号传导的新方法可能在治疗胃肠道疾病的治疗中具有显着的热应用。靶向表观遗传调制代表了一种调节细胞对EGFR信号反应的新方法。来自我们实验室的初步数据，包括无偏的表观遗传shRNA筛查，表明核支架蛋白梅宁及其组蛋白甲基转移酶结合伴侣混合谱系白血病（MLL）对于在EGFR抑制的情况下对于细胞存活至关重要。文献中报道的Menin/MLL和EGFR信号传导之间没有已知的联系，这使我们假设Menin/MLL轴是一种重要的表观遗传机制，可以抑制EGFR信号传导时，可以使包括结肠上皮细胞在内的结肠上皮细胞生存。该假设将在两个相互关联的特定目的中提出：（1）在EGFR抑制的情况下定义了Menin/MLL介导的细胞存活的机制。（2）确定在体内EGFR抑制期间，Menin/MLL对于细胞存活是否重要。该建议将利用体外和体内方法来定义MENIN/MLL和EGFR信号通路之间的串扰，这对于MENIN/MLL介导的细胞在EGFR抑制的情况下至关重要。该创新提案中的实验还将直接应用于开发新疗法，以治疗良性和恶性结直肠疾病，包括炎症性肠病和结肠癌。此外，该研究建议将通过特殊的心态，已经组成的研究咨询委员会以及明确的分区和机构承诺来以综合的方式得到支持。最后，这项K08奖将成为我职业生涯目标最终成就的基础，以成为一个主要的学术医学中心的独立身体科学家。