Genomic instability and DNA repair in a distinct molecular class of prostate canc

前列腺癌独特分子类别中的基因组不稳定性和 DNA 修复

基本信息

批准号：
9294993
负责人：
Christopher E Barbieri
金额：
$ 17.29万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294993
关键词：
Advisory Committees Affect Androgens Binding CHD1 gene Cancer Patient Cell Culture Techniques Cell Line Cells Characteristics Complement Computational Biology DNA DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Rearrangement Disease Double Strand Break Repair Employee Strikes Event Exhibits Experimental Pathology Gene Expression Profiling Gene Fusion Genes Genetic Transcription Genome Stability Genomic DNA Genomic Instability Genomics Genotoxic Stress Human In Vitro Individual Institutes K-Series Research Career Programs Lesion Malignant Neoplasms Malignant neoplasm of prostate Measures Mentors Missense Mutation Modeling Molecular Mutation Oncogenes Oncogenic Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Platinum Play Poison Production Program Development Prostate Proteins Radical Prostatectomy Recurrence Repair Complex Research Research Personnel Research Proposals Research Training Role Sampling Scientist Specimen Stress Surgeon TP53 gene Testing Therapeutic Agents TimeLine Topoisomerase Transgenic Mice Translating Tumor Suppressor Proteins Urologic Oncology Urologist base cancer genomics career career development clinical care cohort design disease classification genomic aberrations in vivo Model inhibitor/antagonist medical schools mouse model mutant novel outcome forecast precision medicine prostate cancer cell public health relevance repaired response skill acquisition tumor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): This five year K08 Career Development Award proposal for Dr. Christopher Barbieri describes a career development program designed to culminate in a career as an independent investigator in Urologic Oncology. Dr. Barbieri is an urologist at Weill Cornell Medical College, committed to a career as a surgeon-scientist focused on the molecular characterization of prostate cancer. This Career Development Award will allow Dr. Barbieri to become an expert in the molecular characterization of prostate cancer, and translate this research into the clinical care of prostate cancer patients. Dr. Barbieri will be mentored by Dr. Mark Rubin, a leader in the field of prostate cancer genomics and molecular classification of the disease. Dr. Rubin is Vice Chair for Experimental Pathology and Director of the Institute for Precision Medicine at Weill Cornell Medical College, and has overseen the career development of numerous young investigators. Research training will be enhanced by an outstanding team of collaborators to allow development of skills in genomics, mouse modeling, and computational biology. Finally, an advisory committee composed of well-recognized individuals serving roles as clinicians, scientists, and institutional leaders will further guide career development. The research proposal focuses on genomic rearrangements, which play a critical role in the pathogenesis of prostate cancer. Recently described recurrent mutations in SPOP define a novel molecular subclass of prostate cancer characterized by striking increases in total genomic rearrangements compared to other subtypes. The central hypothesis of this proposal is that SPOP mutant prostate cancers have distinct management of DNA break formation and repair, leading to effects on genomic rearrangements, altered sensitivity to therapeutic agents, and potentially effects on patient prognosis. Specific Aims include: 1) To elucidate the role of SPOP mutation in the formation and repair of DNA breaks in prostate cells. 2) To determine the effect of SPOP mutation on the sensitivity of prostate cancer cells to therapeutic agents affecting DNA damage and repair. 3) To define the association of SPOP mutations with patient outcomes and deregulation of DNA damage pathways in a large, well annotated cohort of radical prostatectomy specimens. Together, these studies will define the role of SPOP mutations in genomic instability, nominate potential inhibitors of SPOP mutant prostate cancer, and define the effect of SPOP mutation on the outcomes of patients with prostate cancer.

描述（由申请人提供）：克里斯托弗·巴比耶（Christopher Barbieri）博士的五年K08职业发展奖提案描述了一项职业发展计划，旨在在职业生涯中担任泌尿外科肿瘤学独立研究者。 Barbieri博士是Weill Cornell医学院的一名泌尿科医生，他致力于从事外科医生科学家的职业，专注于前列腺癌的分子表征。该职业发展奖将使Barbieri博士能够成为前列腺癌分子表征的专家，并将这项研究转化为前列腺癌患者的临床护理。 Barbieri博士将由前列腺癌基因组学领域的领导者Mark Rubin博士和该疾病的分子分类。 Rubin博士是Weill Cornell医学院的实验病理学副主席和精密医学研究所主任，并负责监督众多年轻调查员的职业发展。杰出的合作者团队将增强研究培训，以允许发展基因组学，鼠标建模和计算生物学的技能。最后，由公认的个人组成的咨询委员会将担任临床医生，科学家和机构领导者的角色，将进一步指导职业发展。研究建议的重点是基因组重排，这些重排在前列腺癌的发病机理中起关键作用。最近描述的SPOP中的复发突变定义了一种新型的前列腺癌分子亚类，其特征是与其他亚型相比，总基因组重排的震荡增加。该提案的中心假设是，汤匙突变体癌症对DNA断裂形成和修复具有明显的管理，从而导致对基因组重排的影响，对治疗剂的敏感性改变以及对患者预后的潜在影响。具体目的包括：1）阐明了汤匙突变在前列腺细胞中DNA断裂的形成和修复中的作用。 2）确定SPOP突变对前列腺癌细胞对影响DNA损伤和修复的治疗剂的敏感性的影响。 3）在大型，注释的前列腺切除术标本中，定义了SPOP突变与患者结局的关联和DNA损伤途径的放松管制。总之，这些研究将定义SPOP突变在基因组不稳定性中的作用，提名SPOP突变前列腺癌的潜在抑制剂，并确定SPOP突变对前列腺癌患者结果的影响。