Molecular Dissection of Cardiovascular Disease: From Genes to Models to Function

心血管疾病的分子解剖：从基因到模型到功能

• 批准号: 8018111
• 负责人: JESSICA J CONNELLY
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-23 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018111
• 关键词: Address; Alleles; Antineoplastic Agents; Aorta; Atherosclerosis; Authorship; Biological Assay; Blood Circulation; Candidate Disease Gene; Cardiovascular Diseases; Cell Aging; Cell Proliferation; Cell division; Cell physiology; Cells; Chromosomes; Collaborations; Collagen Gene; Computer Simulation; Computers; Coronary Arteriosclerosis; DNA; DNA Binding; DNA Methylation; Data; Decitabine; Dissection; Dose; Effectiveness; Endothelial Cells; Ensure; Enzymes; Family; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Goals; Human; Immunoprecipitation; Linkage Disequilibrium; Low-Density Lipoproteins; Manuscripts; Maps; Measures; Methods; Methylation; Modeling; Molecular; Myocardial; Myocardial Infarction; Organism; Paste substance; Pattern; Play; Preparation; Process; Proliferating; Public Health; Publications; Publishing; Risk; Role; Sampling; Simulate; Single Nucleotide Polymorphism Map; Site; Smooth Muscle Myocytes; Theoretical Studies; Time; Topoisomerase II; Topoisomerase-II Inhibitor; Validation; Work; antimicrobial drug; base; case control; comparative; design; genetic linkage; in vivo; inhibitor/antagonist; interdisciplinary approach; interest; member; novel; research study; segregation; theories

Type II topoisomerases are essential enzymes common to all organisms. Their cellular functions include maintaining the levels of chromosome compaction and ensuring proper segregation at cell division. In addition they are often used as targets for antimicrobial agents and anticancer drugs. Understanding the process by which topoisomerase II (topo II) simplifies the topological complexity of its DMA substrate is of key importance. By a cut-and-paste mechanism, which is well understood at the molecular level, topo II is able to pass a DMA segment through another. How topo II recognizes the two DMA segments is still unclear. Topo II is known to unknot and decatenate DMA to levels below those expected by random strand-passage. These and other experimental observations suggest a chirality-driven non-random mechanism of topo II action. Numerous experimental and theoretical studies have addressed these questions. However a clear picture of the mechanism of topo II is still lacking. Our long-term goal is to find an accurate model for the mechanism of topology simplification by topo II. We here focus on the process of DNA unknotting. Our objective is to verify whether topo II has the ability to unknot DMA in the smallest possible number of strand-passages, or whether a chirality bias combined with other local information are sufficient to reach the experimentally observed unknotting levels. We propose an interdisciplinary approach involving a sophisticated theoretical framework based on mathematical knot theory and Monte Carlo computer simulations, and followed by experimental validation. The computer implementation is based on a novel idea which will greatly reduce computation time as compared to other computational models of unknotting. Relevance to Public Health: Our method will give us the ability to efficiently simulate wild-type topo II on any distribution of DNA knots. Besides being of theoretical interest, such modeling is relevant to public health. Unknotting assays are used in the design of anti-cancer drugs to identify new topo II inhibitors. Our work will be applied to quantifying the unknotting capabilities of the topo II of a given organism with and without the presence of an inhibitor, thus establishing a precise measure of the inhibitor's effectiveness.

II型拓扑异构酶是所有生物常见的必需酶。它们的细胞功能包括 保持染色体压实的水平并确保细胞分裂的适当分离。在 此外，它们通常被用作抗菌剂和抗癌药物的靶标。了解 拓扑异构酶II（TOPO II）简化其DMA底物的拓扑复杂性的过程是 关键的重要性。通过在分子水平上得到充分理解的切割机制，Topo II为 能够将DMA段通过另一个段。 Topo II如何识别两个DMA段仍然是 不清楚。众所周知，Topo II可以解开和脱发DMA的水平低于随机预期的水平 链通。这些和其他实验观察表明，手性驱动的非随机 TOPO II动作的机理。许多实验和理论研究已经解决了这些 问题。然而，仍然缺乏清晰的Topo II机理。我们的长期目标是 找到一个准确的模型，以简化拓扑II的拓扑机理。我们在这里专注于 DNA取消的过程。我们的目标是验证Topo II是否能够解开DMA 最小数量的绞线 - 或手性偏见是否与其他局部 信息足以达到实验观察到的未结水平。我们提出了一个 涉及基于数学结的复杂理论框架的跨学科方法 理论和蒙特卡洛计算机模拟，然后进行实验验证。计算机 实施是基于一个新颖的想法，该想法将大大减少与其他的计算时间 无结的计算模型。 与公共卫生相关：我们的方法将使我们能够有效模拟野生型Topo II 关于DNA结的任何分布。除了具有理论上的兴趣外，这种建模与公众有关 健康。抗癌药物的设计用于识别新的TOPO II抑制剂。 通过 并且没有抑制剂，因此建立了抑制剂的精确度量 效力。