Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)

DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)

• 批准号: 10251045
• 负责人: John A. Tainer
• 金额: $ 89.11万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10251045
• 关键词: Abscopal effect; Advanced Malignant Neoplasm; BRCA mutations; BRCA1 gene; Bayesian Method; Biological; Cancer Biology; Cancer Etiology; Cell physiology; Cells; Clinical; Crystallization; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA Structure; Data; Data Set; Databases; Defect; Dissection; Distant; Embryo; Foundations; Funding; Future; Genomic Instability; Image; Immune response; Ionizing radiation; Knowledge; Link; Malignant Neoplasms; Maps; Measurement; Measures; Medicine; Molecular Conformation; Mutation; Outcome; Pathway interactions; Patients; Phenotype; Proteins; Radiation; Repair Complex; Resistance; Resistance development; Resolution; Roentgen Rays; Seminal; Site; Spatial Distribution; Structure; Technology; Testing; Weight; Work; base; cancer therapy; design; experience; human DNA; inhibitor/antagonist; large datasets; nanoscale; neoplastic cell; programs; response; side effect; therapy resistant; tool; tumor

PROJECT SUMMARY/ABSTRACT Cancer is linked to almost every human DNA repair (DR) pathway. Genomic instability, which results from DR defects, is a cancer hallmark. Thus, DNA damaging cancer therapies are widely used and are often successful. Yet, the effects of DNA damage depend on poorly understood DR complexes that are also targets for advanced treatments, e.g. PARP inhibitors that rely on a synthetic lethality (SL) relationship between PARP and BRCA proteins. Although effective initially, these treatments often later fail due to various means of resistance developed in tumors. Thus, better strategies are urgently required to delay or avoid resistance by identifying new SL partners. This revised MANTIS- DRC R35 application will focus on the BRCA paradox (whereby BRCA-defective tumor cells survive yet BRCA inactivation causes cell and embryonic lethality) with implications for future efforts to modulate the DNA damage response to harness the abscopal effect (a paradox whereby ionizing radiation is immunosuppressive yet can activate an immune response to kill tumors distant from the radiation site). We hypothesize that answers to both the 'BRCA paradox' and the ‘abscopal paradox’ lie in changes to DNA damage response that will aid in identifying strategies to tackle resistance. Based upon his NCI-funded experience, Prof. Tainer is poised to build program efforts to efficiently define and test these DR changes that will inform: 1) BRCA essentiality in most cells and SL in tumors and 2) strategies to control the abscopal effect. This work will thus leverage and apply Tainer’s seminal contributions in integrating crystal structures with X-ray scattering to define conformations and assemblies in solution that link structures to phenotypes. Specifically, we will focus on defining a largely enigmatic BRCA1 interactome by producing atomic-resolution structural information and identifying new BRCA1 SL partners: these will be key proteins and interfaces regulating DR pathways (and potentially capable of inducing an abscopal response) that are difficult to overcome via resistance pathways. To elucidate how DR complexes orchestrate cellular processes on DNA, we will integrate structure and imaging to map their spatial distribution and measure their temporal dynamics with systematic and comprehensive analyses. Rather than correlating large data sets, we will rigorously merge suitable data sets via tested Bayesian approaches for integrating data with maximum likelihood weighting according to the relative confidence in each measurement. Leveraging cutting-edge clinical information at MD Anderson will enable testing relevance and impact of our predictions by comparisons with results in patient databases. Anticipated collective results will produce quantitative, objective and mechanistic data to combine measurements from molecules to cells, to design dissection-of-function mutations and inhibitor tools, and to predict biological outcomes.

项目摘要/摘要 癌症几乎与所有人类DNA修复(DR)途径有关。基因组不稳定，导致 患有DR缺陷症，是癌症的标志。因此，DNA损伤癌症疗法得到了广泛的应用和 通常都是成功的。然而，dna损伤的影响取决于人们知之甚少的DR复合体。 也是先进治疗的靶点，例如依赖于合成致死性的PARP抑制剂 (SL)PARP和BRCA蛋白之间的关系。虽然最初有效，但这些治疗方法 通常后来由于肿瘤中产生的各种耐药手段而失败。因此，更好的策略是 迫切需要通过寻找新的SL合作伙伴来推迟或避免阻力。这只修改过的螳螂- DRC R35的应用将集中在BRCA悖论(BRCA缺陷肿瘤细胞存活的悖论 然而，BRCA失活会导致细胞和胚胎死亡)，并对未来的努力产生影响 调节DNA损伤反应以利用非局域效应(电离自相矛盾 放射具有免疫抑制作用，但可以激活免疫反应，杀死远离肿瘤的肿瘤。 辐射场所)。我们假设这既可以回答“金砖四国悖论”，也可以回答“非局部性悖论”。 在于DNA损伤反应的变化，这将有助于确定应对耐药性的策略。 根据他在NCI资助的经验，泰纳教授准备建立一个项目，以有效地 定义并测试这些DR更改，这些更改将提供以下信息：1)BRCA在大多数单元中的重要性，SL在 肿瘤和2)控制异常效应的策略。因此，这项工作将发挥杠杆作用并适用 泰纳在将晶体结构与X射线散射相结合方面的开创性贡献 将结构与表型联系起来的溶液中的构象和组装。具体地说，我们将重点关注 关于通过产生原子分辨结构来定义一个神秘的BRCA1相互作用组 信息和识别新的BRCA1 SL合作伙伴：这些将是关键的蛋白质和接口 调控DR通路(并且潜在地能够引起异常反应)是困难的 通过抵抗途径克服。阐明DR复合体如何协调细胞过程 在DNA上，我们将结合结构和成像来绘制它们的空间分布并测量它们的 具有系统和全面分析的时间动力学。而不是关联大数据 集合，我们将通过用于集成数据的经过测试的贝叶斯方法来严格合并合适的数据集 根据每个测量中的相对置信度进行最大似然加权。 利用MD Anderson的尖端临床信息将使测试具有相关性和影响力 通过与患者数据库中的结果进行比较来验证我们的预测。预期的集体结果将 产生定量的、客观的和机械的数据，以结合从分子到 细胞，设计功能解剖突变和抑制工具，并预测生物学结果。