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: 8548299
• 负责人: Samuel Bunting
• 金额: $ 23.27万
• 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/8548299
• 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： 纠正BRCA1缺陷细胞基因组不稳定性的靶向治疗。 BRCA1或BRCA2基因突变的个体约占5- 发达国家所有乳腺癌的10%。对于携带突变的BRCA1基因的女性来说， 一生中患乳腺癌的几率接近80%，患乳腺癌的几率接近40%。 患上卵巢癌。目前，尚无有效或靶向的分子治疗方法。 改变了这种敏感度。在缺乏BRCA1活性的情况下，细胞无法修复 DNA突破了同源重组途径(HR)。人力资源提供无错误服务 修复DNA损伤的机制，但在缺乏有效的HR的情况下，细胞可以修复DNA 通过其他容易出错的路径进行破坏。这些路径的使用可以导致 形成异常的和潜在有害的染色体结构，促进 肿瘤发生学。事实上，人们普遍认为BRCA1缺陷细胞无法 执行HR是其在肿瘤形成中的核心作用。最近的报告表明，它是 通过缺失DNA的基因来恢复BRCA1缺陷细胞的HR活性 损伤响应系数为53BP1。这些结果表明，在BRCA1缺陷细胞中，53BP1 可能是一种HR的分子抑制剂。此外，抑制53BP1的活性可能会减少 BRCA1介导的乳腺癌的发病率。拟议的研究将探索这部小说 有可能在BRCA1细胞和组织中恢复接近正常的HR活动。 53BP1和BRCA1之间的相互作用将进一步表征，以完善我们的 对潜在机制的理解，以及开发先导化合物的尝试 抑制53BP1的功能。对这一现象的更全面的理解将导致有针对性的 降低BRCA1和潜在BRCA2患者终生肿瘤形成风险的治疗 承运人。