Arid1a loss accelerates pancreatic ductal adenocarcinoma precursor formation

Arid1a缺失加速胰腺导管腺癌前体形成

• 批准号: 10198860
• 负责人: Sam C. Wang
• 金额: $ 16.09万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198860
• 关键词: ARID1A gene; Acinar Cell; Acinus organ component; Advisory Committees; Affect; Award; Cancer Biology; Cells; Child; Chromatin; Chromatin Remodeling Factor; Data; Dependence; Development; Disease; Ductal Epithelial Cell; Environment; Epigenetic Process; Fostering; Genes; Genomics; Goals; Hematopoietic stem cells; Institutes; Intraepithelial Neoplasia; KRAS2 gene; Knowledge; Lesion; Liver Regeneration; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Mentors; Mentorship; Molecular; Molecular Biology Techniques; Mucinous Neoplasm; Mus; Mutate; Mutation; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Papillary; Patient-Focused Outcomes; Patients; Pharmacology; Post-Transcriptional Regulation; Process; Protein Biosynthesis; Proteins; Research; Research Institute; Research Personnel; Resources; Ribosomal Proteins; Role; Sampling; Science; Scientist; Testing; Therapeutic Intervention; Time; Training; Translations; Tumor Angiogenesis; Tumor Suppressor Genes; Tumor Suppressor Proteins; Wages; base; cancer initiation; career development; chromatin remodeling; epigenetic regulation; experience; histone modification; improved; improved outcome; in vivo; loss of function; mortality; multidisciplinary; mutant; new therapeutic target; novel; novel therapeutics; pancreatic cancer patients; pancreatic tumorigenesis; premalignant; prevent; protein expression; recombinase; stem cell biology; therapeutic target; therapeutically effective; tumor metabolism; tumor microenvironment; tumor progression

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.

项目概要/摘要 胰腺导管腺癌 (PDAC) 患者的预期 5 年生存率低于 10% 部分原因是缺乏对驱动分子机制的详细了解。 胰腺癌的形成和进展迫切需要开发新的疗法来治疗这一棘手的问题 ARID1A 是 SWI/SNF 染色质重塑复合物的一部分，是最常见的疾病之一。 PDAC 中的基因发生了突变，但突变的影响尚不清楚，我们发现小鼠中 Arid1a 缺失。 导致胰腺上皮内肿瘤 (PanIN) 的加速形成，这是 PDAC 的前体。 我们还发现 Arid1a 丢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 ARID1A 缺失是如何发生的。 腺泡细胞中的 Arid1a 突变是否加速 PanIN 的形成，通过确定 1) 如果 Arid1a 突变不仅加速 PanIN 的形成以及它们向 PDAC 的进展，2) Arid1a 缺失的表观遗传效应 胰腺，以及3)如果阻断蛋白质合成可以阻止Arid1a诱导的PanIN形成完成。 我们的建议，我们希望我们能够更好地了解 ARID1A 和染色质重塑如何影响胰腺 癌症的发生和进展并可能确定新的治疗靶点。 拟议的项目将成为我继续培训和发展的一部分，以成为一名独立的人 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。 朱浩博士将是我的共同导师，他是一位经验丰富、成就斐然的科学家。 Rolf Brekken 博士是肿瘤微环境和癌症领域的专家。 血管生成和在小鼠胰腺癌研究方面拥有丰富的经验，将是我的共同导师。 科学顾问团队包括 1) Sean Morrison 博士，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）徐健博士，表观遗传学和蛋白质专家 3) Joshua Mendell 博士，Howard Hughes 研究员，转录后基因专家 他们将为我的科学提供指导、职业发展指导和技术支持。 外科承诺保护我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，无论该奖项申请的结果如何。 朱实验室位于儿童研究所，由莫里森博士领导，是一个多学科的实验室。 该研究所专注于干细胞生物学、癌症和新陈代谢，是一个协作性极强的研究所。 资源环境优越，培训环境优良。