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

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于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他的医学博士学位，以及一个高产的博士学位。在斯坦福大学的遗传学系。他花了几年时间共同创立了一家系统生物学公司，Incidity Systems，然后回到医学界，在弗朗西斯科的加州大学皮肤科完成了住院医师项目。作为该部门的一名年轻研究人员，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，候选人将扩大他的科学技能，成为一个独立的研究人员开发新的基因组方法癌症遗传学。他将通过课程作业，参加会议和研讨会系列，国家演讲和指导研究项目的指导来实现这些目标。鲍里斯·巴斯蒂安博士将指导候选人的科学发展。Bastian博士是全国公认的皮肤癌体细胞异常研究专家，并表征了皮肤（KIT）和葡萄膜（GNAQ和GNA 11）黑色素瘤的关键潜在突变。该咨询委员会将由一名国家Notch受体结构和癌症功能专家组成（Jon C.阿斯特，医学博士，博士，病理学教授，布里格姆妇女医院），一个领先的表观遗传学家（约瑟夫科斯特洛博士，医学博士，博士，副教授，加州大学旧金山分校），并在癌症基因组学和表观基因组学的领导者（乔W。Gray博士，Gordon摩尔教授和OHSU生物医学工程主席）。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，揭示了皮肤，头颈部和肺鳞状细胞癌中Notch受体的频繁体细胞突变。由于Notch也激活血液系统癌症，这项工作描绘了第一个已知的组织特异性，双功能肿瘤抑制基因/癌基因。该研究项目将检查其他上皮癌的体细胞Notch突变，并开发精细映射的表达特征，以探索Notch功能的表观遗传背景。将采用下一代DNA和转录组（RNA）测序。汇总数据将提供一系列重要实体癌关键途径状态的详细描述。拟议的培训计划借鉴了UCSF癌症中心和UCSF皮肤科的综合资源。这将为候选人成长为独立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.