Development Project 3

生物医学知识的进步是更迅速的时候，翻译的研究成果可以很容易， 有效地跨越不同的生物组织水平。这一过程需要将基本的 分子见解（基础研究）到新的和应用的临床疗法（"前向翻译"），以及 在群体水平上发现用于特定临床观察的分子机制（"反向 翻译"）。正如领导和行政核心所概述的那样，WFU OAIC的主要目标之一 是开发新的工具，实施研究战略和基础设施，以促进翻译 research.本研究开发项目的主要目标是扩大分子生物学的能力， 科学资源核心（MSRC），通过开发基础设施， 生成、分析和整合关于人类基因表达水平变化的数据 组织对临床干预的反应。这些数据将导致新的假设的产生 关于分子适应和机制的基础上改善物理 将提供一个工具，供审计和调查办公室的调查人员 可以将生物机制的研究纳入其现有的方案中。 拟议的发展项目将通过扩大一个独特的临床 我们最近完成的OAlC支持的随机对照试验研究（"优化身体"）发现 用于老年人功能的组合物; OPTIMA "）。OPTIMA研究旨在评估 将热量限制与过氧化物酶体增殖物激活受体（PPARy）激动剂吡格列宗（pioglitazone）组合 和/或阻力训练对88名社区老年人（65 - 79岁）身体机能和身体成分的影响 超重/肥胖（BMI> 27 kg/m2）成人，随机接受4个月干预：1）单独低热量饮食 （饮食）; 2）饮食加每日30 mg吡格列酮/Actos？（PIO）; 3）饮食加阻力训练（RT）;或4）饮食 我们发现吡格列酮与抗阻训练有显著的相互作用， 在肌肉力量的显着改善，但不是肌肉力量，（见f节），使参与者 随机分配至DIET + PIO + RT组的受试者膝伸肌最大扭矩改善2倍 （肌肉力量）比随机分配至仅饮食+RT的那些。 这一新观察的机制尚不清楚，但可能与基因表达的改变有关。 肌肉对吡格列酮刺激的响应。PPARs是核激素的成员 受体超家族的作用是调节基因转录，这反过来又调节了许多不同的 包括脂质和碳水化合物代谢的过程，以及某些炎症途径。 PPARy配体如吡格列宗的结合可以是组织特异性的，尚未完全理解，并且可能潜在地 包括不依赖于PPARy刺激作用。因此，我们建议利用储存的活检样本， 股外侧肌（在干预之前和之后取）进行基因表达微阵列， 然后进行途径分析，以开始了解这种情况的潜在机制。 互动Loeser博士以前使用微阵列技术的经验， 给定组织的表达谱，再加上系统生物学分析方法（由Dr. Fetrow），是用于鉴定以前未知的基因（以及最终的蛋白质）的理想工具， 与特定临床观察结果存在因果关系。阵列数据和途径分析将与 身体功能的临床测量、脂肪分布（通过DXA和CT）、肌肉的组织学测量（已经 进行中），并检查所选候选基因的表达，以获得完整的 这是干预的效果图。将身体功能结果与该系统方法相结合， 检查机制代表了当前提供全面信息的黄金标准方法 以及对衰老相关的身体功能丧失的潜在机制的进一步了解。

Advancement of biomedical knowledge is more rapid when translation of research findings can easily and efficiently span across different biological levels of organization. This process entails conversion of fundamental molecular insights (basic research) into novel and applied clinical therapies ("forward translation"), as well as discovery of molecular mechanisms for specific clinical observations at the population level ("reverse translation"). As outlined in the Leadership and Administrative Core, one of the primary goals of the WFU OAIC is to develop new tools and implement research strategies and infrastructure for fostering translational research. The main goal of this Research Development Project is to expand the ability of the Molecular Sciences Resource Core (MSRC) to facilitate reverse translational research by developing the infrastructure to generate, analyze, and integrate encompassing data on changes in expression levels of genes in human tissues in response to clinical interventions. These data will lead to the generation of novel hypotheses regarding the molecular adaptations and mechanisms underlying improvements in physical performance/disability in response to such interventions, and will provide a tool by which OAIC investigators can incorporate investigation of biological mechanisms into their existing protocols. The proposed developmental project will accomplish this overall goal by expanding upon a unique clinical finding from our recently completed OAlC-supported randomized, controlled pilot study ("Optimizing body composition for function in older adults; OPTIMA"). The OPTIMA study was designed to assess the effects of combining caloric restriction with the peroxisome proliferator-activated receptor (PPARy) agonist pioglitizone and/or resistance training on physical function and body composition in 88 community-dwelling older (65-79 yrs) overweight/obese (BMI>27 kg/m2) adults randomized to a 4-month intervention of: 1) hypocaloric diet alone (DIET); 2) DIET plus 30 mg daily pioglitizone/Actos¿(PIO); 3) DIET plus resistance training (RT); or 4) DIET plus PIO and RT. We discovered a remarkable interaction of pioglitizone with resistance training that resulted in significant improvements in muscle power, but not muscle strength, (see section f) such that the participants randomized to DIET+PIO+RT experienced a two-fold greater improvement in knee extensor maximal torque (muscle power) than those randomized to DIET+RT only. The mechanism for this novel observation is unknown, but could be related to altered gene expression in muscle in response to stimulation of PPARy by pioglitizone. PPARs are members of a nuclear hormone receptor superfamily that act to regulate gene transcription, which in turn regulates a number of diverse processes including lipid and carbohydrate metabolism, as well as certain inflammatory pathways.1 The effects of PPARy ligands such as pioglitizone can be tissue specific, are not completely understood, and can potentially include effects independent of PPARy stimulation. Therefore, we propose to utilize stored biopsy samples of the vastus lateralis muscle (taken before and after the interventions) to conduct gene expression microarrays, followed by pathway analysis to begin to develop an understanding of the underlying mechanism for this interaction. Dr. Loeser's previous experience in the use of microarray technology, which provides a gene expression profile of a given tissue, coupled with a systems biology analytical approach (contributed by Dr. Fetrow), are ideal tools for the task of identifying previously unknown genes (and ultimately proteins) that may be causally linked to a specific clinical observation. The array data and pathway analysis will be combined with clinical measures of physical function, fat distribution (by DXA and CT), histologic measures of muscle (already in progress), and with examination of the expression of selected candidate genes, in order to gain a complete picture of the effect of the intervention. Integration of physical function outcomes with this systems approach to examining mechanisms represents the current gold standard approach to providing comprehensive information and additional insight into the mechanisms underlying aging-related loss of physical function.