Integrated analysis of Notch pathway loss-of-function in epithelial tumorigenesis

描述(由申请人提供)：本提案描述了一项为期5年的培训计划，旨在发展癌症遗传学领域的学术生涯。这位候选人在斯坦福大学医学院完成了医学博士学位，并在斯坦福大学遗传学系获得了卓有成效的博士学位。他花了几年时间共同创立了一家名为Inenuity Systems的系统生物学公司，然后回到医学界，在加州大学旧金山分校皮肤病系完成了一个住院医生项目。作为该部门的一名年轻研究员，他撰写了两篇原创研究文章，阐明了鳞状细胞癌的分子进展。通过拟议的培训计划，候选人将扩展他的科学技能，成为一名独立的研究员，开发癌症遗传学的新基因组方法。他将通过课程作业、参加系列会议和研讨会、国家报告和指导一个有指导的研究项目来实现这些目标。鲍里斯·巴斯蒂安博士将指导候选人的科学发展。巴斯蒂安博士是全国公认的皮肤癌躯体异常研究专家，他描述了皮肤(KIT)和葡萄膜(GNAQ和GNA11)黑色素瘤的关键潜在突变。咨询委员会将由一位癌症Notch受体结构和功能方面的国家专家(布里格姆妇女医院病理学教授乔恩·C·埃斯特博士，医学博士，博士)、一位主要的表观遗传学家(加州大学旧金山分校副教授约瑟夫·科斯特洛博士)和一位癌症基因组和表观基因组学的领导者(乔·W·格雷博士，博士，戈登·摩尔教授兼俄亥俄州立大学生物医学工程主席)组成。研究将集中在新发现的Notch受体及其下游信号通路在上皮性肿瘤发生中的作用。最近的研究，包括候选人领导的一项研究，揭示了皮肤、头颈部和肺的鳞状细胞癌中Notch受体的频繁体细胞突变。由于Notch还会激活血液病癌症，这项工作描绘了第一个已知的组织特异性、双功能肿瘤抑制/癌基因。该研究项目将检查其他上皮性癌症的体细胞Notch突变，并开发精细映射的表达特征，以探索Notch功能的表观遗传学背景。将采用DNA和转录组(RNA)的下一代测序。汇总的数据将提供一系列重要实体癌症关键路径状态的详细描述。拟议的培训计划利用了加州大学旧金山分校癌症中心和加州大学旧金山分校皮肤科的联合资源。这将为候选人成为一名独立的调查员提供理想的环境。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in the field of cancer genetics. The candidate completed his M.D at the Stanford University School of Medicine, as well as a highly productive Ph.D. in the Department of Genetics at Stanford. He spent several years co-founding a systems biology company, Ingenuity Systems, before returning to medicine to complete a residency program in the Department of Dermatology at the University of California, San Francisco. As a young investigator in the department, he has authored two original research articles illuminating the molecular progression of squamous cell carcinomas. Through the proposed training program, the candidate will expand upon his scientific skills to become an independent investigator developing new genomic approaches to cancer genetics. He will meet these goals through coursework, participation in conferences and seminar series, national presentations, and steerage of a mentored research project. Dr. Boris Bastian will mentor the candidate's scientific development. Dr. Bastian is a nationally recognized expert in study of somatic abnormalities in skin cancers and has characterized key underlying mutations in cutaneous (KIT) and uveal (GNAQ and GNA11) melanoma. The advisory committee will consist of a national expert in Notch receptor structure and function in cancer (Dr. Jon C. Aster, MD, PhD, Professor of Pathology, Brigham and Women's Hospital), a leading epigeneticist (Dr. Joseph Costello, MD, PhD, Associate Professor, UCSF), and a leader in cancer genomics and epigenomics (Dr. Joe W. Gray, PhD, Gordon Moore Professor and Chair, Biomedical Engineering, OHSU). Research will focus on the newly discovered role of the Notch receptor and downstream signaling pathway in epithelial tumorigenesis. Recent studies, including one led by the candidate, have revealed frequent somatic mutation of Notch receptors in squamous cell carcinomas of the skin, head-and-neck, and lung. Because Notch also activates hematologic cancers, this work delineates the first known tissue-specific, bifunctional tumor suppressor/oncogene. The research project will examine other epithelial cancers for somatic Notch mutation and develop fine-mapped expression signatures to explore the epigenetic context of Notch function. Next-generation sequencing of DNA and transcriptome (RNA) will be employed. The aggregate data will provide a detailed portrait of the state of a critical pathway across a series of important solid cancers. The proposed training program draws on the combined resources of the UCSF Cancer Center and the UCSF Department of Dermatology. This will provide an ideal setting for the candidate's maturation into an independent investigator.