Development Project 3

当研究成果的翻译可以很容易地和 有效地跨越不同生物层次的组织。这一过程需要转换基本的 对新的和应用的临床疗法的分子见解(基础研究)(“正向翻译”)，以及 在群体水平上发现特定临床观察的分子机制(反转 正如《领导和行政核心》中所概述的，WFU OAIC的主要目标之一 是开发新的工具并实施研究战略和基础设施，以促进翻译 研究。这项研究开发计划的主要目标是扩大分子的能力 科学资源核心(MSRC)，通过开发基础设施来促进反向翻译研究 生成、分析和整合有关人类基因表达水平变化的全面数据 组织对临床干预的反应。这些数据将导致新假说的产生 关于分子适应和物理基础改进的机制 对这类干预措施作出反应的业绩/残疾，并将提供一种工具，供审查处调查人员 可以将对生物机制的研究纳入其现有的方案。 拟议的开发项目将通过扩展一个独特的临床项目来实现这一总体目标 从我们最近完成的由OALC支持的随机、受控的试点研究中发现了这一点 老年人的功能成分；OPTIMA“)。OPTIMA研究旨在评估 联合热量限制和PPARy激动剂吡格列酮 88名社区老年人(65~79岁)身体机能和身体成分的抵抗训练 超重/肥胖(BMI和GT；27公斤/平方米)成年人随机接受为期4个月的干预：1)只接受低热量饮食 (饮食)；2)饮食加每天30毫克的吡格列酮/安慰剂(PIO)；3)饮食加耐力训练(RT)；或4)饮食 加上PIO和RT。我们发现吡格列酮与抵抗训练有显著的相互作用 在肌肉力量方面的显著改善，但不是肌肉力量(见f节)，使得参与者 随机分为饮食+PIO+RT组，在膝关节伸肌最大扭矩方面有两倍的改善 (肌肉力量)比那些随机接受饮食+RT的人要好。 这一新发现的机制尚不清楚，但可能与基因表达的改变有关。 肌肉对吡格列酮刺激PPARy的反应。PPAR是核荷尔蒙的成员 受体超家族，起到调节基因转录的作用，进而调节许多不同的 包括脂肪和碳水化合物代谢的过程以及某些炎症途径1的影响 PPARy的配体，如吡格列酮，可以是组织特异性的，不完全被理解，并且可能 包括与PPARy刺激无关的效果。因此，我们建议利用储存的活体组织样本 股外侧肌(干预前后取)进行基因表达微阵列， 然后进行路径分析，以开始了解其潜在的机制 互动。勒泽博士之前使用微阵列技术的经验，这种技术提供了一种基因 特定组织的表达谱，结合系统生物学分析方法(由Dr。 Fetrow)，是识别以前未知的基因(最终是蛋白质)的理想工具 与特定的临床观察有因果关系。阵列数据和路径分析将与 临床测量身体功能、脂肪分布(通过DXA和CT)、肌肉组织学测量(已 正在进行中)，并检查选定的候选基因的表达，以便获得完整的 干预效果的图景。将身体机能结果与这种系统方法相结合 审查机制代表了当前提供全面信息的黄金标准方法 以及对与衰老相关的身体功能丧失的潜在机制的更多见解。

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.