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.

项目总结/摘要 癌症与几乎所有人类DNA修复（DR）途径有关。基因组的不稳定性， 是癌症的标志。因此，DNA损伤癌症疗法被广泛使用， 往往是成功的。然而，DNA损伤的影响取决于知之甚少的DR复合物 也是高级治疗的靶点，例如依赖于合成致死性的PARP抑制剂 (SL)PARP和BRCA蛋白的关系。虽然最初有效，但这些治疗方法 由于肿瘤中产生的各种耐药性，通常随后失败。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耐药性。这一修订版的MANTIS- DRC R35申请将重点关注BRCA悖论（BRCA缺陷型肿瘤细胞存活 然而BRCA失活导致细胞和胚胎死亡），这对未来的努力有影响， 调节DNA损伤反应以利用远位效应（一个悖论， 辐射是免疫抑制性的，但可以激活免疫反应，杀死远离肿瘤的肿瘤。 辐射部位）。我们假设“BRCA悖论”和“远位悖论”的答案 改变DNA损伤反应，这将有助于确定应对耐药性的策略。 根据他的NCI资助的经验，泰纳教授准备建立计划的努力，以有效地 定义并测试这些DR变化，这些变化将告知：1）大多数细胞中的BRCA重要性和 肿瘤和2）控制远位效应的策略。因此，这项工作将发挥杠杆作用， 泰纳的开创性贡献是将晶体结构与X射线散射结合起来， 在溶液中连接结构和表型的构象和组装。具体来说，我们将重点 通过产生原子分辨率的结构， 信息和识别新的BRCA 1 SL合作伙伴：这些将是关键蛋白质和接口 调节DR途径（并可能诱导远位反应），这是困难的 通过抵抗途径克服。阐明DR复合物如何协调细胞过程 在DNA上，我们将结合结构和成像来绘制它们的空间分布图，并测量它们的 时间动力学与系统和全面的分析。而不是将大量数据 集，我们将严格合并合适的数据集通过测试贝叶斯方法整合数据 根据每个测量中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能够测试相关性和影响力 通过与患者数据库中的结果进行比较，预期的集体成果将 产生定量的、客观的和机械的数据，以将分子测量联合收割机结合起来， 细胞，设计功能突变和抑制剂工具，并预测生物学结果。