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

 描述（由申请人提供）：通过表皮生长因子受体（EGFR）的信号传导在结肠上皮稳态和疾病中很重要。因此，寻找新的方法来调节EGFR信号传导可能对治疗胃肠道疾病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信号传导应答的新方法。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伴侣混合谱系白血病（MLL）在EGFR抑制的情况下对细胞存活至关重要。在文献中报道的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轴作为重要的表观遗传机制，使结肠上皮衍生的细胞包括结肠癌细胞在EGFR信号传导被抑制时存活。这一假设将在两个相互关联的具体目标中进行：（1）定义在EGFR抑制的情况下menin/MLL介导的细胞存活的机制。(2)确定在体内EGFR抑制期间，menin/MLL是否对细胞存活重要。该提案将利用体外和体内方法来定义在EGFR抑制的情况下对于menin/MLL介导的细胞存活至关重要的menin/MLL和EGFR信号传导途径之间的串扰。这项创新提案中的实验也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，这一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，以综合的方式得到支持。最后，这个K 08奖将作为我最终实现职业目标的基础，成为一个主要学术医疗中心的独立医生科学家。

 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.