Human Biology Core, Project 10 of 10

人类生物学核心，项目 10（共 10 个）

• 批准号: 7886537
• 负责人: EDWARD Harry LIVINGSTON
• 金额: $ 35.01万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886537
• 关键词: Area; Basic Science; Bioinformatics; Biological; Biomedical Engineering; Cells; Cellular biology; Clinic; Computer software; Cultured Cells; Data; Databases; Development; Endocrinology; Environment; Functional disorder; Goals; Heart; Hepatic; Human; Human Biology; Individual; Insulin; Kinetics; Knowledge; Lipids; Lipoproteins; Measurement; Metabolic; Metabolic syndrome; Methods; Mitochondria; Modeling; Modification; Modus; Molecular; Molecular Genetics; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Patients; Perioperative; Physiology; Protocols documentation; Publishing; Recruitment Activity; Research; Research Personnel; Science; Signal Transduction; Skeletal Muscle; Techniques; Technology; Testing; Tissue Banking; Tissue Banks; Tissues; Translational Research; Translations; Ursidae Family; design; experience; feeding; human subject; human tissue; medical schools; mouse model; multidisciplinary; muscle metabolism; nutrition; professor; programs; response; stable isotope; tool; volunteer

One of the principal TORS goals is integration of new metabolic, genetic, and molecular cell biological data, collected using multiple technologies in mouse models and human subjects, into a mechanistic understanding of key aspects of obesity and type II diabetes. To advance this goal, we have formed a public-private research partnership between the four TORS teams and an NIH-supported software and kinetic modeling company, Integrative Bioinformatics Inc (IBI). IBI's software product, ProcessDB, is a tool for managing the development of large scale quantitative mechanistic models and testing these simultaneously against multiple experimental protocols using diverse measurement technologies. Dr. Phair, a former professor of biomedical engineering and physiology at the Johns Hopkins School of Medicine, and his colleagues at IBI have many years of experience with these techniques at levels of biological organization from whole human subjects to cultured cells. They have published in many relevant areas including lipid and lipoprotein metabolism, endocrinology/nutrition, and molecular cell biology. To reach the long term goal of an integrated mechanistic model of key aspects of the physiology and pathophysiology of obesity, the modeling effort will draw from and contribute to each of the TORS subprojects. Initially, however, we plan to focus on integration of information from two TORS teams: Parks and Malloy (Burgess, Browning). To our knowledge, this will be the first integration of metabolic information from well-established NMR and G.C/MS techniques in the same human subjects and patients. Leveraging the unique strengths of both stable isotope methods is unprecedented. In years 02-05 we plan to expand these inter-team projects to include: 1) Selection of informative human subjects (Cohen/Hobbs) from the Dallas Heart Study to be analyzed using the GC/MS (Parks) and NMR (Malloy) technologies, and fitted to our developing integrated model using constraints from known genetic defects in these individuals. 2) Development of a parallel metabolic model for relevant aspects of mouse physiology and pathophysiology. This parallel development will facilitate translation of basic research in the mouse model to testable hypotheses in human subjects and patients. 3) Completion of a model of skeletal muscle metabolism including mitochondrial function (Malloy), that can be combined with the hepatic model to produce an integrated model of two major organs/tissues involved in the metabolic response to feeding and insulin. By putting the ProcessDB software on each Pi's desktop, all TORS groups will have constant access to the developing integrated models and will be able to propose modifications and additions to be tested. They can also add to the ProcessDB database new experimental protocols and data. ProcessDB will thus serve as a focused mechanistic "knowledge environment" for the TORS program, along the same lines as the signal transduction knowledge environment (STKE) developed by AAAS/Science. (http://stke.sciencemag.org/).

TORS的主要目标之一是整合新的代谢、遗传和分子细胞生物学数据， 在小鼠模型和人类受试者中使用多种技术收集， 肥胖和II型糖尿病的关键方面。为了推进这一目标，我们成立了一个公私合作的研究小组， 四个TORS团队与NIH支持的软件和动力学建模公司之间的合作， Integrative Bioinformatics Inc（IBI）. IBI的软件产品ProcessDB是一种管理开发的工具， 大规模的定量机制模型，并测试这些同时对多个实验 使用多种测量技术的协议。Phair博士曾是生物医学工程教授， 约翰霍普金斯医学院的生理学博士和他在IBI的同事们有多年的经验， 从整个人类个体到培养细胞的生物组织水平上使用这些技术。他们 发表了许多相关领域的文章，包括脂质和脂蛋白代谢，内分泌学/营养学， 分子细胞生物学为了实现长期目标的综合机制模式的关键方面， 肥胖的生理学和病理生理学，建模工作将借鉴并有助于每一个 TORS分项目。然而，最初，我们计划将重点放在整合来自两个TORS团队的信息上： 帕克斯和马洛伊（伯吉斯，布朗宁）。据我们所知，这将是第一次整合代谢 在相同的人类受试者和患者中，来自成熟的NMR和G.C/MS技术的信息。 利用这两种稳定同位素方法的独特优势是前所未有的。在2002 -05年，我们计划 扩展这些团队间的项目，包括：1）选择信息人类受试者（科恩/霍布斯）从 使用GC/MS（Parks）和NMR（Malloy）技术分析达拉斯心脏研究，并拟合我们的 利用这些个体中已知遗传缺陷的约束条件开发综合模型。2)发展 小鼠生理学和病理生理学相关方面的平行代谢模型。这个平行 发展将促进小鼠模型中的基础研究转化为人类可检验的假设， 受试者和患者。3)完成包括线粒体功能的骨骼肌代谢模型 （Malloy），其可以与肝脏模型组合以产生两个主要的模型的集成模型。 参与对进食和胰岛素的代谢反应的器官/组织。通过安装ProcessDB软件， 在每个Pi的桌面上，所有TORS小组都将不断访问正在开发的集成模型， 能够提出修改和添加进行测试。他们还可以向ProcessDB数据库中添加新的 实验方案和数据。因此，ProcessDB将作为一个集中的机械“知识环境”。 对于TORS计划，沿着与信号转导知识环境（STKE）相同的路线 由AAAS/Science开发。(http：//stke.sciencemag.org/）。