AN INTEGRATED APPROACH TO PREDICTING ONCOGENIC MUTATIONS IN NOVEL BREAST CANCER

预测新型乳腺癌致癌突变的综合方法

• 批准号: 8364289
• 负责人: Rachel Karchin
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364289
• 关键词: 1-Phosphatidylinositol 3-Kinase; Automobile Driving; Biomedical Research; Boxing; Breast; Catalytic Domain; Development; Funding; Grant; High Performance Computing; Human; In Vitro; Location; Malignant Neoplasms; Mutate; Mutation; National Center for Research Resources; Oncogenic; PIK3CA gene; Phosphotransferases; Principal Investigator; Protein Isoforms; Proteins; Reporting; Research; Research Infrastructure; Resources; Solvents; Somatic Mutation; Source; Structure; System; United States National Institutes of Health; Water; Work; cost; gain of function; in vivo; insight; malignant breast neoplasm; molecular dynamics; novel; simulation; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Somatic mutations in PIK3CA (phosphatidylinositol-3 kinase, catalytic subunit, alpha isoform) are reported in breast and other human cancers to concentrate at hotspots within its kinase and helical domains. Most of these mutations cause kinase gain of function in vitro and are associated with oncogenicity in vivo. However, little is known about the mechanisms driving tumor development. Recent work has suggested the existence of three distinct mechanisms that produce an oncogenic PIK3CA protein depending on the structural location of the mutated residue. We propose that we can gain insight on the structural impact of oncogenic somatic mutations in PIK3CA and the existence of this multiple mechanism hypothesis by exploring conformational changes that result from these mutations using extensive molecular dynamics simulations. Our simulations will involve the PIK3CA crystal structure that contains both the PIK3CA catalytic and regulatory subunits, solvated in an explicit water solvent box resulting in the total system size of ~305063 atoms.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 据报道，PIK 3CA（磷脂酰肌醇-3激酶，催化亚基，α亚型）的体细胞突变在乳腺癌和其他人类癌症中集中在其激酶和螺旋结构域内的热点。这些突变中的大多数在体外引起激酶功能的获得，并且与体内致癌性相关。然而，对驱动肿瘤发展的机制知之甚少。最近的研究表明，存在三种不同的机制，根据突变残基的结构位置产生致癌PIK 3CA蛋白。我们建议，我们可以深入了解致癌的体细胞突变在PIK 3CA的结构影响和存在这种多重机制的假设，通过探索构象变化，这些突变导致使用广泛的分子动力学模拟。我们的模拟将涉及PIK 3CA晶体结构，其包含PIK 3CA催化亚基和调节亚基，在明确的水溶剂盒中溶剂化，导致总系统尺寸为~305063个原子。