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.

项目概要/摘要 癌症几乎与所有人类 DNA 修复 (DR) 途径有关，从而导致基因组不稳定。 DR 缺陷是癌症的一个标志，因此，DNA 损伤性癌症疗法被广泛使用和使用。 然而，DNA 损伤的影响往往取决于人们对 DR 复合物知之甚少。 这也是先进治疗的目标，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 虽然这些治疗方法最初有效，但 由于肿瘤中产生的各种耐药手段，后来常常失败，因此，更好的策略是。 迫切需要通过确定新的 SL 合作伙伴来延迟或避免抵抗。 DRC R35应用将重点关注BRCA悖论（BRCA缺陷的肿瘤细胞存活 然而，BRCA 失活会导致细胞和胚胎死亡），这对未来的努力具有影响 调节 DNA 损伤反应以利用远隔效应（这是一个悖论，因此电离 辐射具有免疫抑制作用，但可以激活免疫反应来杀死远离肿瘤的肿瘤。 我们勇敢地回答了“BRCA 悖论”和“远隔悖论”。 关键在于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 NCI 资助的经验，Tainer 教授准备开展项目工作，以高效地 定义并测试这些 DR 变化，这些变化将告知：1) 大多数细胞中 BRCA 的重要性以及 SL 中的重要性 肿瘤和2）控制远隔效应的策略因此将利用和应用。 Tainer 在将晶体结构与 X 射线散射相结合以定义晶体结构方面做出了开创性的贡献 具体来说，我们将重点关注解决方案中将结构与表型联系起来的构象和组装。 通过产生原子分辨率的结构来定义一个很大程度上神秘的 BRCA1 相互作用组 信息并确定新的 BRCA1 SL 伙伴：这些将是关键的蛋白质和界面 调节 DR 通路（并且可能能够诱导远隔反应）是困难的 阐明 DR 复合物如何协调细胞过程。 在DNA上，我们将整合结构和成像来绘制它们的空间分布并测量它们 通过系统和全面的分析来分析时间动态，而不是关联大数据。 集，我们将通过经过测试的贝叶斯方法严格合并合适的数据集以集成数据 根据每次测量的相对置信度进行最大似然加权。 利用 MD 安德森的尖端临床信息将实现测试的相关性和影响 通过与患者数据库中的结果进行比较，我们的预测将得到预期的集体结果。 产生定量和机械数据，将分子测量结果结合起来 细胞，设计功能突变和抑制剂工具，并预测生物学结果。