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。

基本信息

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
项目类别：
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

项目摘要

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 基因突变的个体大约占 5- 占发达国家所有乳腺癌的 10%。对于携带突变 BRCA1 基因的女性，一生中有近 80% 的机会患上乳腺癌，近 40% 的机会患上乳腺癌发展为卵巢癌。目前尚无有效或靶向的分子疗法改变这种敏感性。在缺乏 BRCA1 活性的情况下，细胞无法修复 DNA突破同源重组途径(HR)。 HR提供无错误修复DNA损伤的机制，但在缺乏有效HR的情况下，细胞可以修复DNA 通过其他容易出错的途径造成损害。使用这些途径可以导致异常和潜在有害的染色体结构的形成，促进肿瘤发生。事实上，人们普遍认为 BRCA1 缺陷细胞无法执行 HR 对其在肿瘤形成中的作用至关重要。最近的报告表明，通过删除 DNA 基因可以恢复 BRCA1 缺陷细胞中的 HR 活性损伤响应因子，53BP1。这些结果表明，在 BRCA1 缺陷细胞中，53BP1 可能作为 HR 的分子抑制剂。此外，抑制 53BP1 活性可能会降低 BRCA1 介导的乳腺癌的发病率。拟议的研究将探索新颖的认为 BRCA1 细胞和组织中的 HR 活性可能恢复到接近正常水平。 53BP1 和 BRCA1 之间的相互作用将被进一步表征，以完善我们的研究了解潜在机制，并尝试开发先导化合物抑制 53BP1 功能。更全面地了解这一现象将有助于有针对性地降低 BRCA1 和潜在 BRCA2 肿瘤形成终生风险的疗法载体。