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

描述（由申请人提供）：此提案描述了一个在癌症遗传学领域发展学术生涯的5年培训计划。这位候选人在斯坦福大学医学院获得了医学博士学位，并在斯坦福大学遗传学系获得了高产的博士学位。他花了几年时间与人共同创立了一家系统生物学公司Ingenuity systems，之后回到医学界，在加州大学旧金山分校（University of California, San Francisco）皮肤科完成了住院医师项目。作为该系的年轻研究员，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者，开发新的癌症遗传学基因组方法。他将通过课程学习、参加会议和研讨会系列、全国演讲和指导一个受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。他是全国公认的皮肤癌体细胞异常研究专家，并描述了皮肤（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Notch受体在癌症中的结构和功能方面的国家专家（Jon C. Aster博士，医学博士，病理学教授，Brigham and Women's Hospital），一位领先的表观遗传学家（Joseph Costello博士，医学博士，副教授，UCSF），以及癌症基因组学和表观基因组学的领导者（Joe W. Gray博士，Gordon Moore教授和OHSU生物医学工程主席）组成。研究将集中在新发现的Notch受体和下游信号通路在上皮肿瘤发生中的作用。最近的研究，包括由候选人领导的一项研究，已经揭示了Notch受体在皮肤、头颈部和肺部鳞状细胞癌中频繁的体细胞突变。由于Notch也激活血液学癌症，这项工作描述了第一个已知的组织特异性、双功能肿瘤抑制/致癌基因。该研究项目将研究其他上皮癌的体细胞Notch突变，并开发精细的表达特征，以探索Notch功能的表观遗传背景。下一代DNA和转录组（RNA）测序将被采用。综合数据将提供一系列重要实体癌关键通路状态的详细描述。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综合资源。这将为候选人成长为一名独立调查员提供一个理想的环境。

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.