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

 描述(申请人提供)：通过表皮生长因子受体(EGFR)的信号在结肠上皮细胞动态平衡和疾病中很重要。因此，寻找新的方法来调节EGFR信号转导可能对胃肠道疾病的治疗具有重要的应用价值。靶向性表观遗传调控是调控细胞对EGFR信号反应的一种新方法。来自我们实验室的初步数据，包括无偏倚的表观遗传shRNA筛选，表明核支架蛋白Menin及其组蛋白甲基转移酶结合伙伴混合谱系白血病(MLL)在EGFR抑制的背景下对细胞生存至关重要。文献报道的MENIN/MLL和EGFR信号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学机制，当EGFR信号被抑制时，它能够使包括结肠癌细胞在内的结肠上皮源性细胞存活。这一假说将在两个相互关联的特定目标下进行：(1)在EGFR抑制的背景下，确定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起重要作用。这项建议将利用体外和体内的方法来确定MENIN/MLL和EGFR信号通路之间的串扰，在EGFR抑制的背景下，MENIN/MLL介导的细胞生存至关重要。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的新疗法，包括炎症性肠病和结肠癌。此外，这项研究提案将通过特殊的指导、一个已经成立的研究咨询委员会以及明确的部门和机构承诺，以综合方式得到支持。最后，这个K08奖项将作为我最终实现职业目标的基础，成为一名主要学术医学中心的独立内科医生兼科学家。

 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.