Development Project 3

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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.