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Mechanisms of the BRCA-network in tumorigenesis and therapeutic response

BRCA 网络在肿瘤发生和治疗反应中的机制

基本信息

批准号：
10396606
负责人：
Zhiyuan Shen
金额：
$ 227.02万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396606
关键词：
Ablation Address Area BARD1 gene BRCA1 gene BRCA2 gene Cells Chromatin Chromosomal Stability Chromosomes Clinical Collaborations Complex DNA Damage DNA Repair DNA Sequence DNA Sequence Alteration DNA biosynthesis DNA replication fork Data Defect Development Epigenetic Process Functional disorder Generations Genes Genetic Genetically Engineered Mouse Genomic Instability Genomics Goals Human Impairment In Vitro Kinetics Lead MCM10 gene Malignant Neoplasms Mammalian Cell Mammary Neoplasms Mediating Methods Methylation Modeling Molecular Mus Mutagenesis Mutation PALB2 gene Pathway interactions Pattern Pharmaceutical Preparations Program Research Project Grants Proteins Recurrence Regulation Research Research Personnel Resolution Resource Sharing Role Site Structure Suggestion Sumoylation Pathway TOP1 gene TOPBP1 Gene Therapeutic Tumor Suppression Ubiquitination base cancer therapy chemotherapy design gene network genome integrity genomic signature genomic tools homologous recombination improved improved outcome inhibitor insight interdisciplinary approach interest loss of function malignant breast neoplasm medulloblastoma member mouse model mutant novel novel therapeutics p53-binding protein 1 programs public health relevance recruit repaired replication stress response success targeted cancer therapy targeted treatment tool treatment response tumor tumorigenesis ubiquitin-protein ligase

项目摘要

Mechanisms of the BRCA-network in Tumorigenesis and Therapeutic Response (OVERALL) Abstract: The faithful repair of DNA damage and efficient resolution of stalled replication forks are fundamental mechanisms by which mammalian cells maintain DNA sequence fidelity and chromosomal integrity during DNA replication and in response to exogenous DNA damage. Defects in DNA repair mechanisms not only contribute to genomic instability and subsequent tumorigenesis, but also can alter the epigenetic landscape of cells and impart therapeutic vulnerabilities that can be exploited clinically. The investigators participating in this P01 project share common interests in understanding the mechanisms by which cells maintain genomic integrity to suppress tumorigenesis, and in exposing tumor vulnerability to therapy based on mechanistic understandings of the genomic consequences of impaired DNA repair. One particularly strong area of research offered by this team is a multi-disciplinary approach to understanding the basic mechanisms by which the BRCA1-PALB2-BRCA2 complex and associated regulators participate in regulating DNA replication and repair choice. Regulators of the BRCA-network include, 53BP1, RNF4, BARD1, TOPBP1, EHMT2 (G9a), MCM10, SLFN11 (mouse Slfn9), and BCCIP. Some of these factors have been a long-standing research focus for investigators in the project team. The research collaboration is formed around the central themes of how members of this large network of proteins interface with each other to maintain genome integrity, suppress tumor development and modulate tumor response to cancer therapy. Four projects, two Shared Resource Cores, and an Administrative Core are proposed to achieve three scientific goals: 1) to reveal novel mechanisms by which the recruitment and function of the BRCA1-PALB2-BRCA2 network is regulated by chromatin context mediated by methylation, sumoylation, and ubiquitination; 2) to refine the roles of the BRCA network in DNA replication, tumor suppression and define the genomic consequences of BRCA dysfunction; and 3) to explore new opportunities to target defects in the BRCA network for therapeutics in medulloblastoma and breast cancer.

brca网络在肿瘤发生和治疗反应中的作用机制（OVERALL）