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

• 批准号: 9319748
• 负责人: Bryson William Katona
• 金额: $ 16.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9319748
• 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; beta catenin; cancer cell; carcinogenesis; career; cell growth; colitis associated cancer; direct application; epigenetic regulation; experimental study; histone methyltransferase; improved; in vivo; injury and repair; innovation; knock-down; leukemia; mouse model; novel; novel therapeutics; overexpression; public health relevance; response; small hairpin RNA; villin

 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（由申请人提供）：通过表皮生长因子受体（EGFR）的信号传导对于结肠上皮稳态和疾病很重要。因此，寻找调节 EGFR 信号传导的新方法可能对胃肠道疾病的治疗具有重要的治疗应用。靶向表观遗传调节代表了一种调节细胞对 EGFR 信号传导反应的新方法。我们实验室的初步数据（包括无偏见的表观遗传 shRNA 筛选）表明，核支架蛋白 menin 及其组蛋白甲基转移酶结合伴侣混合谱系白血病 (MLL) 对于 EGFR 抑制情况下的细胞存活至关重要。文献中报道的 menin/MLL 和 EGFR 信号传导之间没有已知的联系，这导致我们假设 menin/MLL 轴是一种重要的表观遗传机制，使结肠上皮衍生细胞（包括结肠癌细胞）在 EGFR 信号传导受到抑制时能够存活。这一假设将在两个相互关联的具体目标中得到实现：(1) 定义在 EGFR 抑制的情况下 menin/MLL 介导的细胞存活的机制。 (2) 确定 menin/MLL 在体内 EGFR 抑制过程中是否对细胞存活很重要。该提案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 EGFR 抑制情况下 menin/MLL 介导的细胞存活至关重要。这项创新提案中的实验还将直接应用于开发治疗良性和恶性结直肠疾病（包括炎症性肠病和结肠癌）的新疗法。此外，该研究提案将通过卓越的指导、已经成立的研究咨询委员会以及明确的部门和机构承诺得到综合支持。最后，这个 K08 奖项将成为我最终实现职业目标的基础，成为主要学术医学中心的独立医师科学家。