Multi-scale imaging of breast cancer proteins during DNA repair

DNA 修复过程中乳腺癌蛋白的多尺度成像

基本信息

批准号：
10183192
负责人：
Deborah F Kelly
金额：
$ 40.77万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183192
关键词：
Address Affect Architecture BARD1 gene BRCA1 Mutation BRCA1 Protein BRCA1 gene Binding Biochemical Biological Assay Breast Cancer Cell Cancer Patient Cell Nucleus Cell Survival Cells Clinical Co-Immunoprecipitations Confocal Microscopy Cryoelectron Microscopy DNA DNA Damage DNA Repair Data Data Collection Defect Detection Development Disease Electrons Elements Ensure Estrogens Event Genetic Materials Genetic Transcription Genome Genomic Instability Hot Spot Human Image Imaging Device Imaging technology Incidence Inherited Link Malignant Neoplasms Malignant neoplasm of ovary Maps Molecular Molecular Structure Morphology Motion Mutate Mutation Nuclear Outcome Pathology Patients Phenotype Predisposition Prevention Process Proteins Publishing RNA Polymerase II Reagent Recurrence Repair Complex Research Resolution Role Scientific Inquiry Structure Structure-Activity Relationship Testing Time Titan Tumor Suppressor Proteins Visualization Western Blotting Woman Work base biochemical tools breast imaging cancer cell cancer risk carcinogenesis clinically relevant design detector experimental study genome integrity insight live cell imaging malignant breast neoplasm microscopic imaging molecular modeling nanometer new therapeutic target oxidative damage protein structure repaired response targeted treatment therapeutic target tool triple-negative invasive breast carcinoma

项目摘要

PROJECT SUMMARY/ABSTRACT Mutations in the breast cancer susceptibility protein, BRCA1, are heavily linked to the development of triple negative breast and ovarian cancer phenotypes. Currently, there are no precise treatments to mitigate the detrimental effects of BRCA1 mutations in triple negative cancer patients, and recurrence rates for this disease are higher than in any other form of breast cancer. In the nucleus, BRCA1 helps protect the genome by its involvement in DNA repair processes, thus serving as a tumor suppressor. However, cells harboring BRCA1 mutations lose the ability to properly repair DNA damage and transcribe their genome. The culmination of these events leads to genomic instability and eventually cancer induction. The precise manner in which mutated BRCA1 fails to execute its functions remains unclear. Understanding the molecular basis for these defects could provide significant insight toward developing new targeted therapies for BRCA1-related cancers. Based on our preliminary data derived from biochemical experiments, cryo-Electron Microscopy (EM) imaging, and molecular modeling routines, we believe differences in cancer development are related to morphological changes in the BRCA1 protein structure. Simply stated, mutations in BRCA1 that alter its structural elements will reduce its ability to engage other proteins during DNA repair. To investigate this idea at the subcellular level, we will utilize multi-scale imaging technology ranging from confocal microscopy to high-resolution cryo- EM. Combining this visualization information with rigorous biochemical analysis, we will develop a unique molecular-based approach to delineate the multifaceted role of BRCA1 in cancer formation. We also expect to define new opportunities to design targeted therapies based on mechanistic insights gathered at the molecular level of scientific inquiry.

项目概要/摘要乳腺癌易感蛋白 BRCA1 的突变与三联体的发展密切相关乳腺癌和卵巢癌阴性表型。目前尚无精确的治疗方法来缓解 BRCA1 突变对三阴性癌症患者的不利影响以及该疾病的复发率高于任何其他形式的乳腺癌。在细胞核中，BRCA1 通过其作用来帮助保护基因组参与 DNA 修复过程，从而充当肿瘤抑制因子。然而，携带 BRCA1 的细胞突变失去了正确修复 DNA 损伤和转录基因组的能力。的顶峰这些事件导致基因组不稳定并最终诱发癌症。准确的方式突变的 BRCA1 无法执行其功能仍不清楚。了解这些的分子基础缺陷可以为开发 BRCA1 相关癌症的新靶向疗法提供重要见解。根据我们从生化实验、冷冻电子显微镜 (EM) 成像中获得的初步数据，和分子建模程序，我们相信癌症发展的差异与形态学有关 BRCA1 蛋白质结构的变化。简单地说，BRCA1 中的突变改变了其结构元件会降低其在 DNA 修复过程中与其他蛋白质结合的能力。为了在亚细胞中研究这个想法在水平上，我们将利用从共焦显微镜到高分辨率冷冻的多尺度成像技术 EM。将这些可视化信息与严格的生化分析相结合，我们将开发出独特的基于分子的方法来描述 BRCA1 在癌症形成中的多方面作用。我们也期望根据分子生物学中收集的机制见解确定设计靶向治疗的新机会科学探究的水平。