Human Biology Core, Project 10 of 10

人类生物学核心，项目 10（共 10 个）

• 批准号: 8138151
• 负责人: EDWARD Harry LIVINGSTON
• 金额: $ 6.5万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138151
• 关键词: Human; Biology; Core; Project; 10

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/).

主要TOR目标之一是整合新的代谢，遗传和分子细胞生物学数据，即 在鼠标模型和人类受试者中使用多种技术收集到机械理解 肥胖和II型糖尿病的关键方面。为了促进这一目标，我们成立了一项公私研究 四个TOR团队与NIH支持的软件和动力学建模公司之间的合作关系， 综合生物信息学公司（IBI）。 IBI的软件产品ProcessDB是管理开发的工具 大规模定量机械模型和同时测试这些模型 使用各种测量技术的协议。 Phair博士，前生物医学工程教授和 约翰·霍普金斯医学院的生理学和他在IBI的同事有很多年的经验 从整个人类受试者到培养细胞的生物组织水平上的这些技术。他们 已经在许多相关领域发表，包括脂质和脂蛋白代谢，内分泌学/营养以及 分子细胞生物学。达到关键方面集成机械模型的长期目标 肥胖的生理学和病理生理学，建模工作将借鉴并为每个 TORS子标题。但是，最初，我们计划专注于两个TOR团队的信息集成： 公园和马洛伊（伯吉斯，勃朗宁）。据我们所知，这将是代谢的第一个整合 来自同一受试者和患者的公认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都是前所未有的。在02-05年，我们计划 将这些团队间项目扩展到：1）从 达拉斯心脏研究将使用GC/MS（Parks）和NMR（Malloy）技术进行分析，并适合我们 使用这些个体中已知遗传缺陷的约束来开发集成模型。 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 开发将促进小鼠模型中基础研究的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），可以与肝模型结合使用，以产生两个主要模型 器官/组织参与对喂养和胰岛素的代谢反应。通过将ProcessDB软件放在 每个Pi的桌面，所有TOR组都将不断访问开发的集成模型，并且将是 能够提出要测试的修改和添加。他们还可以添加到ProcessDB数据库新 实验协议和数据。因此，ProcessDB将充当集中的机械“知识环境” 对于TORS程序，与信号转导知识环境（STKE）相同的线 由AAAS/Science开发。 （http://stke.sciencemag.org/）。