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: 7956356
• 负责人: Rachel Karchin
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956356
• 关键词: 1-Phosphatidylinositol 3-Kinase; Automobile Driving; Biomedical Research; Boxing; Breast; Catalytic Domain; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; Grant; High Performance Computing; Human; In Vitro; Institution; Location; Malignant Neoplasms; Mutate; Mutation; Oncogenic; PIK3CA gene; Phosphotransferases; Protein Isoforms; Proteins; Reporting; Research; Research Personnel; Resources; Solvents; Somatic Mutation; Source; Structure; System; United States National Institutes of Health; Water; Work; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 据报道，乳腺癌和其他人类癌症中 PIK3CA（磷脂酰肌醇-3 激酶、催化亚基、α 同工型）的体细胞突变集中在其激酶和螺旋结构域内的热点处。大多数这些突变会导致激酶在体外获得功能，并与体内致癌性相关。然而，人们对肿瘤发展的驱动机制知之甚少。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 PIK3CA 蛋白。我们建议，通过使用广泛的分子动力学模拟探索这些突变引起的构象变化，我们可以深入了解 PIK3CA 中致癌体细胞突变的结构影响以及这种多重机制假说的存在。我们的模拟将涉及 PIK3CA 晶体结构，其中包含 PIK3CA 催化和调节亚基，在显式水溶剂盒中溶剂化，导致总系统大小约为 305063 个原子。