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

• 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
• 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

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）：这五年K08职业发展奖的建议，克里斯托弗Barbieri博士描述了职业发展计划，旨在达到职业生涯的高潮作为一个独立的研究者在泌尿肿瘤学。Barbieri博士是威尔康奈尔医学院的泌尿科医生，致力于从事外科医生科学家的职业生涯，专注于前列腺癌的分子特征。这个职业发展奖将使Barbieri博士成为前列腺癌分子特征的专家，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和疾病分子分类领域的领导者Mark Rubin博士指导。Rubin博士是威尔康奈尔医学院实验病理学副主席兼精密医学研究所所长，并监督了许多年轻研究人员的职业发展。研究培训将由一个优秀的合作者团队加强，以允许在基因组学，小鼠建模和计算生物学的技能发展。最后，由临床医生、科学家和机构领导人组成的咨询委员会将进一步指导职业发展。 该研究计划的重点是基因组重排，这在前列腺癌的发病机制中起着关键作用。最近描述的复发性突变SPOP定义了一种新的前列腺癌分子亚型，其特征是与其他亚型相比总基因组重排显著增加。该建议的中心假设是SPOP突变型前列腺癌对DNA断裂形成和修复具有不同的管理，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SPOP突变在前列腺细胞DNA断裂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)在一个大型的、注释良好的根治性直肠癌切除术样本队列中，确定SPOP突变与患者结局和DNA损伤途径失调的相关性。 总之，这些研究将确定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预后的影响。