Arid1a loss accelerates pancreatic ductal adenocarcinoma precursor formation

项目摘要/摘要 胰腺导管腺癌(PDAC)患者的预期5年生存率不到10%。 部分原因是缺乏有效的治疗方法。详细了解驱动程序的分子机制 胰腺癌的形成和发展迫切需要为这种棘手的疾病开发新的治疗方法。 疾病。ARID1A是SWI/SNF染色质重塑复合体的一部分，是最常见的 PDAC中的基因发生了突变，但突变的影响尚不清楚。我们在小鼠体内发现ARID1A基因缺失 导致胰腺上皮内肿瘤(Panin)的加速形成，而Panin是PDAC的先兆。 我们还发现ARID1a丢失后蛋白质合成异常增加，这表明蛋白质 翻译可能是一种治疗靶点。这项研究的总体目标是确定ARID1A缺失是如何 在腺泡细胞中通过确定1)如果ARID1A突变不仅加速了 Panin的形成及其向PDAC的进展，2)ARID1A缺失在 3)阻断蛋白质合成是否能阻止ARID1A诱导的Panin的形成。在完成时 我们的建议，我们希望我们将更好地了解ARID1A和染色质重塑如何影响胰腺 癌症的发生和发展，并有可能确定新的治疗靶点。 提议的项目将是我继续培训和发展成为一名独立的 调查员。培训计划包括课程作业、实践经验和团队的封闭式指导 经验丰富、成就卓著的科学家。朱浩博士将是我的共同导师。他是扮演……角色的专家 SWI/SNF与肝再生和癌症罗尔夫·布雷肯博士，肿瘤微环境和 血管生成和在研究小鼠胰腺癌方面有丰富的经验，将是我的共同导师。我的 科学顾问团队包括肖恩·莫里森博士，霍华德·休斯研究员和 造血干细胞生物学，包括蛋白质合成，2)表观遗传学和蛋白质专家徐健博士 合成3)霍华德·休斯研究员、转录后基因专家约书亚·门德尔博士 监管。他们将为我的科学提供指导，为我的职业发展提供指导，并提供技术支持。 外科致力于保护我80%的时间用于研究工作，全力支持 我的工资，并维持这些安排，无论这个奖项申请的结果如何。 朱的实验室设在莫里森博士领导的儿童研究所。它是一门多学科的学科 专注于干细胞生物学、癌症和新陈代谢的研究所。这是一个令人难以置信的合作和良好的- 资源环境，是优秀的培训环境。

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) patients have an expected 5-year survival of less than 10% in large part to the lack of effective therapeutics. Detailed understanding of the molecular mechanisms that drive pancreas cancer formation and progression are desperately needed to develop new therapies for this intractable disease. ARID1A, which is part of the SWI/SNF chromatin remodeling complex, is one of the most commonly mutated genes in PDAC but the effects of the mutation are unknown. We found that Arid1a deletion in mouse leads to accelerated formation of pancreatic intraepithelial neoplasms (PanIN), which are precursors to PDAC. We also found that protein synthesis is aberrantly elevated after Arid1a loss, which suggests that protein translation may be a therapeutic target. The overall objective of this study is to determine how ARID1A deletion in acinar cells accelerates the formation PanIN by determining 1) if Arid1a mutations accelerate not only the formation of PanIN but also their progression to PDAC, 2) the epigenetic effects of Arid1a deletion in the pancreas, and 3) if blocking protein synthesis can prevent Arid1a induced PanIN formation. At the completion of our proposal, we expect that we will better understand how ARID1A and chromatin remodeling affect pancreas cancer initiation and progression and potentially identify new therapeutic targets. The proposed project will be part of my continued training and development to become an independent investigator. The training plan includes coursework, hands-on experience, and closed mentorship from a team of experienced and accomplished scientists. Dr. Hao Zhu will be my co-mentor. He is an expert in the role of SWI/SNF in liver regeneration and cancer. Dr. Rolf Brekken, an expert in tumor microenvironment and angiogenesis and has extensive experience studying pancreas cancer in mice, will be my co-mentor. My scientific advisory team includes 1) Dr. Sean Morrison, a Howard Hughes Investigator and an expert in hematopoietic stem cell biology, including protein synthesis, 2) Dr. Jian Xu, an expert in epigenetics and protein synthesis 3) Dr. Joshua Mendell, a Howard Hughes Investigator and an expert in post-transcription gene regulation. They will provide guidance for my science, mentorship for career development, and technical support. The Department of Surgery has committed to protecting 80% of my time for research endeavors, fully supporting my salary, and maintaining these arrangements regardless of the outcome of this award application. The Zhu lab is based in the Children’s Research Institute, which is headed by Dr. Morrison. It is a multidisciplinary institute that focuses on stem cell biology, cancer, and metabolism. It is an incredibly collaborative and well- resourced environment and is an outstanding training environment.