Human Biology Core, Project 10 of 10

人类生物学核心，项目 10（共 10 个）

• 批准号: 8106124
• 负责人: JEFFREY D BROWNING
• 金额: $ 35.12万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106124
• 关键词: American Association for the Advancement of Science; 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; United States National Institutes of Health; 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， 使用多种技术在小鼠模型和人类受试者中收集，以形成机械理解 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研究机构 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伙伴关系， 综合生物信息学公司（IBI）。 IBI 的软件产品 ProcessDB 是一个管理开发的工具 大规模定量机制模型并同时针对多个实验进行测试 使用不同测量技术的协议。 Phair 博士，前生物医学工程教授 约翰·霍普金斯大学医学院的生理学博士，以及他在 IBI 的同事拥有多年的经验 在从整个人类受试者到培养细胞的生物组织层面上使用这些技术。他们 在许多相关领域发表过文章，包括脂质和脂蛋白代谢、内分泌学/营养学和 分子细胞生物学。实现关键方面的综合机制模型的长期目标 肥胖的生理学和病理生理学，建模工作将借鉴并贡献于每一个 TORS 子项目。然而，最初我们计划重点关注两个 TORS 团队的信息整合： 帕克斯和马洛伊（伯吉斯，布朗宁）。据我们所知，这将是新陈代谢的首次整合 来自相同人类受试者和患者的成熟 NMR 和 G.C/MS 技术的信息。 利用两种稳定同位素方法的独特优势是前所未有的。在 02-05 年，我们计划 扩展这些团队间项目以包括： 1）从 达拉斯心脏研究将使用 GC/MS (Parks) 和 NMR (Malloy) 技术进行分析，并安装到我们的 利用这些个体已知遗传缺陷的约束开发综合模型。 2）发展 小鼠生理学和病理生理学相关方面的并行代谢模型。这个平行 开发将有助于将小鼠模型的基础研究转化为可在人类中测试的假设 受试者和患者。 3）完成包括线粒体功能在内的骨骼肌代谢模型 （Malloy），可以与肝脏模型结合产生两个主要的集成模型 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 每个 Pi 的桌面上，所有 TORS 小组都将能够持续访问正在开发的集成模型，并且将 能够提出要测试的修改和添加。他们还可以向 ProcessDB 数据库添加新的 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，与信号转导知识环境 (STKE) 相同 由美国科学促进会/科学开发。 （http://stke.sciencemag.org/）。

项目成果

Insulin activation of plasma nonesterified fatty acid uptake in metabolic syndrome.

• DOI: 10.1161/atvbaha.112.250019
• 发表时间: 2012-08
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Ramos-Roman MA;Lapidot SA;Phair RD;Parks EJ
• 通讯作者: Parks EJ

Pitfalls in using BMI as a selection criterion for bariatric surgery.

使用 BMI 作为减肥手术选择标准的陷阱。

• DOI: 10.1097/med.0b013e328357f0b8
• 发表时间: 2012
• 期刊: Current opinion in endocrinology, diabetes, and obesity
• 作者: Livingston,EdwardH

Variations of weight loss following gastric bypass and gastric band.

胃绕道手术和胃束带术后体重减轻的变化。

• DOI: 10.1097/sla.0b013e3181820cbc
• 发表时间: 2008
• 期刊: Annals of surgery
• 影响因子: 9
• 作者: Puzziferri,Nancy;Nakonezny,PaulA;Livingston,EdwardH;Carmody,ThomasJ;Provost,DavidA;Rush,AJohn
• 通讯作者: Rush,AJohn