Age-Induced Impairment of Nutrient Signaling Results in Bone Loss

DESCRIPTION (provided by applicant): One out of every six adults over the age of sixty-five consumes less than 1,000 calories/day, and in the case of older, institutionalized populations the prevalence of malnutrition increases to between twenty-three to sixty percent. It Is precisely this population that is at greatest risk for bone fractures. We hypothesize that a decline in musculoskeletal function with age is due in large part to a decline in nutrient-activated anabolic signals. This Program Project application is focused on defining the role of nutrients in age-dependent bone loss. The proposal consists of three Projects and three Core facilities. The three research projects will define the molecular mechanisms involved in nutrient modulation of bone marrow stromal cell (BMSC) differentiation and proliferation, and will determine how these mechanisms are altered with aging. The three Core facilities will add value to the program as a whole by providing essential support to the Projects while at the same time promoting aging and bone research at the Medical College of Georgia. The overall specific aims of the proposal are: (1) To determine how aging alters the response of bone-derived progenitor cells to amino acids;(2) To determine how aging alters the response of bone-and muscle-derived stem cells to nutrition-related hormones (e.g., IGF-1 and leptin);and (3) To determine how aging and nutrient-related stimuli alter the transcriptional regulation of BMSC differentiation mediated by stromal derived factor-1. Major strengths of this application include: (1) a multidisciplinary team of investigators with diverse backgrounds in molecular biology, physiology, endocrinology, and bone biology, who will bring new perspectives to solve a common problem;(2) a strong clinical-translational focus, with both M.D. clinician scientists and Ph.D. research scientists playing key roles;(3) a mixture of investigators of diverse background and training who have been working together for five years;(4) outstanding institutional support from both clinical and research departments, as well as from the MCG administration;and (5) the coordinated use of a common model of aging mice (C57BL/6) across highly integrated project components. This tight integration among the different projects makes this proposal truly synergistic and unique. Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function. PUBLIC HEALTH RELEVANCE: The studies described here will aid in the development of new strategies to treat and prevent age related bone loss. REVIEW OF INDIVUDUAL COMPONENTS CORE A: ADMINISTRATIVE AND BIOSTATISTICS CORE;Dr. Carlos Isales, Core Leader (CL). DESCRIPTION (provided by applicant): Administrative and biostatistical activities of the Program Project will take place in the Administrative Core. Drs. Isales and Hamrick will be responsible for the scientific oversight of the PPG, the direction of research emphasis and the fiscal administration. Dr. Isales will chair the Executive and Scientific Committee meetings and be responsible for preparing all progress reports for these two committees and for the NIA. Dr. Isales will consult with appropriate committee members and Project and Core Leaders in order to effectively resolve all personnel and fiscal issues that may arise. Dr. Isales will be the liaison to the NIA and will ensure that annual non-competing renewal reports and quarterly reports on participant accrual are reported promptly and accurately to the NIA. He will also oversee compliance with regard to MCG's Institutional Review Board's policies, including the requirement that all Project and Core investigators and staff maintain certification in MCG's Research Ethics Training Program. The main purpose of the Biostatistics component is to bring together the information from different sources into an integrated database, and to coordinate the statistical analyses with the focus being on the main goals of the PPG.The Biostatistics faculty will help the investigators of the projects to choose appropriate experimental designs and analytical techniques tailored to address specific hypotheses, especially, focusing on justification of the data analysis method to be used for each type of data generated. The Biostatistics component will serve as the focus for data compilation, quality control, data analysis and interpretation support for the PPG, including: 1. Design and apply analytical methods to be used in the quantitative studies associated with various projects in the PPG;2. Provide ongoing statistical consultation to research projects, focusing on issues such as experimental design, sample size, aptness and validity of models to be used, power considerations, interpretation of results and preparation of manuscripts for presentations and publications;and 3. Maintain a dataflow system that insures accuracy, security, validation and archiving of all data collected for different projects of the PPG. PUBLIC HEALTH RELEVANCE: Core A will ensure that the Projects receive adequate support both for administrative issues and biostatistical analysis.