Arid1a loss accelerates pancreatic ductal adenocarcinoma precursor formation

项目总结/摘要 胰腺导管腺癌（PDAC）患者的预期5年生存率低于10%， 部分原因是缺乏有效的治疗方法。详细了解分子机制， 胰腺癌的形成和发展迫切需要开发新的治疗方法， 疾病ARID 1A是SWI/SNF染色质重塑复合物的一部分，是最常见的染色质重塑复合物之一。 PDAC中的突变基因，但突变的影响是未知的。我们发现小鼠Arid 1a基因缺失 导致胰腺上皮内肿瘤（PanIN）的加速形成，PanIN是PDAC的前体。 我们还发现，Arid 1a缺失后蛋白质合成异常升高，这表明蛋白质 翻译可能是一个治疗靶点。本研究的总体目标是确定ARID 1A缺失 通过确定1）如果Arid 1a突变不仅加速了PanIN的形成， PanIN的形成以及它们向PDAC的进展，2）Arid 1a缺失的表观遗传效应， 胰腺，和3）如果阻断蛋白质合成可以防止Arid 1a诱导的PanIN形成。完成时 我们的建议，我们希望我们将更好地了解ARID 1A和染色质重塑如何影响胰腺 癌症的发生和发展，并可能发现新的治疗靶点。 建议的项目将是我继续培训和发展的一部分，以成为一个独立的 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 有经验有成就的科学家朱浩博士将是我的共同导师。他是一个专家的作用， SWI/SNF在肝再生和癌症中的作用Rolf Brekken博士是肿瘤微环境专家， 他是一位血管生成专家，在研究小鼠胰腺癌方面有丰富的经验，他将成为我的共同导师。我 科学顾问团队包括1）肖恩莫里森博士，一个霍华德休斯研究员和专家， 造血干细胞生物学，包括蛋白质合成，2）徐建博士，表观遗传学和蛋白质专家 合成3）约书亚门德尔博士，霍华德休斯研究员和转录后基因专家 调控他们将为我的科学提供指导，为职业发展提供指导，并提供技术支持。 外科部门承诺保护我80%的时间用于研究工作，完全支持 我的工资，并保持这些安排，无论这个奖项的申请结果。 朱教授的实验室设在儿童研究所，由莫里森博士领导。这是一个多学科的 该研究所专注于干细胞生物学、癌症和新陈代谢。这是一个令人难以置信的合作和良好的- 资源丰富的环境，是一个优秀的培训环境。

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.