Targeted therapies to correct genomic instability in Brca1-deficient cells.

纠正 Brca1 缺陷细胞基因组不稳定性的靶向治疗。

• 批准号: 8528236
• 负责人: Samuel Bunting
• 金额: $ 24.9万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528236
• 关键词: Accounting; Affect; Alleles; Animals; BRCA2 gene; Binding; Breast; Cells; Chromatin; Chromosome Structures; Clinical; Clinical Research; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Data; Defect; Development; Disease; Ethnic Origin; Excision; Failure; Future; Gene Deletion; Genes; Genetic; Genetic Predisposition to Disease; Genomic Instability; Goals; Histones; Human; Incidence; Individual; Intervention; Knock-in Mouse; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; Molecular Target; Mus; Mutagenesis; Mutation; Nonhomologous DNA End Joining; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Recovery; Reporting; Repression; Research; Risk; Role; Somatic Cell; Study Subject; Tertiary Protein Structure; Testing; Tissues; Woman; abstracting; base; early onset; high risk; high throughput screening; homologous recombination; human 53BP1 protein; in vivo; inhibitor/antagonist; lifetime risk; malignant breast neoplasm; mouse model; mutant; novel; novel strategies; outcome forecast; prevent; repaired; research study; response; restoration; small molecule; tumor; tumorigenesis

Project Abstract: Targeted therapies to correct genomic instability in BRCA1-deficient cells. Individuals with mutations in either the BRCA1 or BRCA2 gene account for approximately 5- 10% of all breast cancers in the developed world. For women carrying a mutant BRCA1 gene, there is a nearly 80% lifetime chance of developing breast cancer and a nearly 40% chance of developing ovarian cancer. At present, there are no effective or targeted molecular therapies that modify this susceptibility. In the absence of BRCA1 activity, cells are incapable of repairing DNA breaks through the homologous recombination pathway (HR). HR provides an error free mechanism to repair DNA damage, but in the absence of efficient HR, cells can repair DNA damage though other error-prone pathways. The use of these pathways can lead to the formation of abnormal and potentially harmful chromosomal structures that promote tumorigenesis. Indeed, it is generally believed that the inability of BRCA1 deficient cells to perform HR is central to its role in tumor formation. Recent reports have demonstrated that it is possible to restore HR activity in BRCA1 deficient cells by deletion of the gene for the DNA damage response factor, 53BP1. These results suggest that in BRCA1-deficient cells, 53BP1 may act as a molecular inhibitor of HR. Furthermore, inhibiting 53BP1 activity may reduce the incidence of BRCA1-mediated breast cancer. The proposed research will explore the novel notion that it may be possible to restore near normal HR activity in BRCA1 cells and tissues. The interplay between 53BP1 and BRCA1 will be further characterized to refine our understanding of the underlying mechanism, as well as an attempt to develop lead compounds that inhibit 53BP1 function. A fuller understanding of this phenomenon will lead to targeted therapies to reduce the lifetime risk of tumor formation in BRCA1 and potentially BRCA2 carriers.

项目摘要： 针对BRCA1缺陷细胞中基因组不稳定性的靶向疗法。 BRCA1或BRCA2基因中突变的个体约为5-- 发达国家的所有乳腺癌中有10％。对于携带突变BRCA1基因的女性 近80％的终身机会患乳腺癌，近40％的机会 发展卵巢癌。目前，没有有效或靶向的分子疗法 这改变了这种敏感性。在没有BRCA1活性的情况下，细胞无法修复 DNA突破了同源重组途径（HR）。人力资源提供了无错误 修复DNA损伤的机制，但是在没有有效的HR的情况下，细胞可以修复DNA 损坏其他容易出错的途径。这些途径的使用可能导致 促进异常和潜在有害染色体结构的形成 肿瘤发生。确实，通常认为BRCA1缺乏细胞无法 执行HR对于其在肿瘤形成中的作用至关重要。最近的报告表明这是 通过删除DNA的基因，可以恢复BRCA1缺乏细胞中的HR活性 损伤响应因子，53BP1。这些结果表明，在BRCA1缺陷细胞中，53BP1 可以充当HR的分子抑制剂。此外，抑制53BP1活性可能会降低 BRCA1介导的乳腺癌的发生率。拟议的研究将探索小说 观点是，在BRCA1细胞和组织中，可能可以恢复正常的HR活性。 53BP1和BRCA1之间的相互作用将进一步描述以完善我们的 了解基本机制，以及尝试开发铅化合物的尝试 抑制53BP1功能。对这种现象的更深入的了解将导致目标 降低BRCA1肿瘤形成寿命风险的疗法和潜在的BRCA2 载体。