Genetics of Sessile Serrated Polyps

无蒂锯齿状息肉的遗传学

• 批准号: 9139434
• 负责人: Manish Gala
• 金额: $ 18.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139434
• 关键词: Accounting; Advisory Committees; Agreement; Alleles; Animal Disease Models; Animal Model; Award; BRAF gene; Cancer Biology; Cancer Center; Cell Cycle; Clinical; Clinical Investigator; Clinical Research; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; Complement; Computer software; Coupled; DNA Damage; Data; Development; Disease; Engineering; Ensure; Environment; European; Funding; Gastroenterologist; Gastroenterology; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genomic DNA; Genomics; Genotype; Goals; Growth; Health; High-Risk Cancer; Human; Human Genetics; Hydrocephalus; Hyperplasia; In Vitro; Incidence; Individual; Intestines; KRAS2 gene; Knock-out; Knockout Mice; Laboratories; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mentors; Mentorship; Metabolic; Microscopy; Molecular; Mus; Mutation; Nature; Neoplasms; Nonsense Mutation; Oncogenes; Pathogenesis; Pathway interactions; Patient risk; Persons; Phenotype; Physicians; Polyps; Population; Precancerous Polyp; Prevalence; Public Health Schools; Publications; RNA Splicing; Research; Research Personnel; Risk; Role; Scientist; Series; Serrated Adenoma; Signal Transduction; Site; Supervision; Susceptibility Gene; Syndrome; Systems Biology; Technology; Time; Translational Research; Translations; Tubular formation; Tumor Suppressor Proteins; Variant; Work; burden of illness; career; career development; ciliopathy; cohort; computer program; crypt cell; data modeling; design; exome sequencing; experience; genetic epidemiology; genomic data; high risk; human data; in vitro Model; in vivo; in vivo Model; indexing; infancy; innovation; intestinal crypt; loss of function; loss of function mutation; mouse model; multidisciplinary; next generation sequencing; novel; overexpression; paralogous gene; patient oriented research; polyposis; professional atmosphere; programs; rare variant; research study; response; screening; senescence; skills; success; translational study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The candidate is an accomplished gastroenterology fellow with a prior background in cancer biology and a commitment to a career in clinical and translational research in the study of sessile serrated polyps. The candidate's long-term career goal is to become an independently funded physician scientist, devoting more than 75% of his time to establish and maintain a clinical research program in gastrointestinal cancer precursor lesions. The candidate's short-term career goals are to 1) build large longitudinal cohort coupled with host genetic data; 2) design and interpret genetic data, including development of novel genomics software; 3) develop mouse models of cancer derived from human genetic data 4) acquire new laboratory skills in DNA damage signaling and microscopy 5) produce the data and publication record necessary for a successful R01 application. This application outlines the institutional commitment, research plan, career development activities and key mentors involved to ensure the candidate accomplishes these goals. In prior work, the candidate has demonstrated that individuals with serrated polyposis harbor germline loss-of-function mutations in key senescence pathways. This finding, in agreement with mouse models, provides the first genetic framework for the heritable nature of serrated polyposis. Nonetheless, data regarding the genetic influences for the development of sporadic sessile serrated polyps are lacking. In this proposal, the candidate seeks to identify such genetic factors through a translation approach of human genetics, animal models, and in vitro experiments. The specific goals of this study are to 1) estimate the contribution of rare loss-of-function mutations in oncogene-induced senescence pathways in the development of sessile serrated polyps in average-risk individuals and 2) evaluate the mechanism through in vivo and in vitro experiments by which a newly implicated tumor suppressor promotes the development of serrated neoplasia. As an integral part of this proposal, the candidate's career development will be complemented by participation in advanced coursework and research seminars to develop expertise in genetic epidemiology, systems biology, and computer programming. A formal mentorship committee and advisory team, consisting of multidisciplinary experts in next-generation sequencing technologies, genetic epidemiology, mouse models of disease, and the microscopy will provide supervision, guidance, and assistance for the candidate to achieve his goals. The research environment, which includes the MGH GI Unit, MGH Cancer Center, and the Harvard School of Public Health will provide a rich, collaborative, and supportive atmosphere to ensure the candidate's success. Through this award, the candidate will become an independent clinical investigator by contributing to our understanding of the genetics of serrated polyps through a series of translational studies that leverage human genetic data with in vivo and in vitro models.

描述（由申请人提供）：候选人是一位出色的胃肠病学研究员，具有癌症生物学背景，并致力于无蒂锯齿状息肉研究的临床和转化研究。该候选人的长期职业目标是成为一名独立资助的医师科学家，投入超过 75% 的时间来建立和维护胃肠癌前驱病变的临床研究项目。候选人的短期职业目标是：1）建立大型纵向队列与宿主遗传数据相结合； 2）设计和解释遗传数据，包括开发新型基因组学软件； 3) 开发源自人类遗传数据的小鼠癌症模型 4) 获得 DNA 损伤信号传导和显微镜学方面的新实验室技能 5) 生成成功 R01 应用所需的数据和出版记录。该申请概述了确保候选人实现这些目标的机构承诺、研究计划、职业发展活动和关键导师。在之前的工作中，该候选人已经证明，患有锯齿状息肉病的个体在关键的衰老途径中存在种系功能丧失突变。这一发现与小鼠模型一致，为锯齿状息肉病的遗传性提供了第一个遗传框架。尽管如此，仍缺乏关于散发性无蒂锯齿状息肉发展的遗传影响的数据。在该提案中，候选人试图通过人类遗传学、动物模型和体外实验的转化方法来识别此类遗传因素。本研究的具体目标是 1) 估计癌基因诱导的衰老途径中罕见的功能丧失突变在平均风险个体无蒂锯齿状息肉发展中的贡献，2) 通过体内和体内评估该机制新发现的肿瘤抑制因子促进锯齿状肿瘤发展的体外实验。作为该提案的一个组成部分，候选人的职业发展将通过参加高级课程和研究研讨会来补充，以发展遗传流行病学、系统生物学和计算机编程方面的专业知识。由下一代测序技术、遗传流行病学、小鼠疾病模型和显微镜等领域的多学科专家组成的正式导师委员会和咨询团队将为候选人实现其目标提供监督、指导和帮助。研究环境包括麻省总医院胃肠病室、麻省总医院癌症中心和哈佛大学公共卫生学院，将提供丰富、协作和支持的氛围，以确保候选人的成功。通过该奖项，候选人将成为一名独立的临床研究者，通过一系列利用体内和体外模型的人类遗传数据的转化研究，为我们对锯齿状息肉遗传学的理解做出贡献。