PROJECT SUMMARY/ABSTRACT - OVERALL Conditions such as osteoporosis and osteoarthritis, and malignancies such as breast cancer, negatively affect the musculoskeletal system, leading to substantial disability and health care costs. Thus, there is an ongoing need to better understand the causes of these conditions and to support development of more effective and well-tolerated therapies. The Center for Musculoskeletal Disease Research (CMDR) was established at the University of Arkansas for Medical Sciences (UAMS) during Phase 1 to meet this need. The scientific theme of the CMDR is that identification of molecular contributors to musculoskeletal dysfunction and disease will guide development of effective therapies. To study these conditions, we have assembled teams of junior and established investigators and supported development of junior investigators to the point of achieving independent R01-level funding. We also utilize state-of-the-art technologies to analyze gene expression, genetically manipulate animals, and analyze the skeleton. These complementary approaches, together with access to clinical investigators and patient samples, have synergized to create a unique and productive research environment. A key to the continued success of the Center will be to increase the number of investigators whose research is aligned with our scientific theme via development of more junior investigators and recruitment of new and established investigators. To accomplish this, in Phase 2 we propose to support the development of 3 Project Leaders by providing structured mentoring, financial resources, and collaboration with other CMDR investigators (Aim 1). We will also continue to strengthen the biomedical research infrastructure at UAMS by increasing the capabilities and utilization of 4 research cores that provide access to rapid, high-quality services and that develop new approaches, such as CRISPR interference for in vivo loss-of-function studies (Aim 2). To continue building a critical mass of musculoskeletal investigators and teams, the Center will utilize a Pilot Project Program, targeted recruitment of investigators with complementary expertise, and incorporation of new and established center investigators into synergistic and productive research teams (Aim 3). Successful implementation of this Organization and Management Plan will, in the long-term, lead to a self-sustaining Center of Biomedical Research Excellence that will generate novel and important results leading to more effective therapies for the numerous conditions that involve the musculoskeletal system.

PROJECT NARRATIVE Conditions such as osteoporosis, osteoarthritis, osteomyelitis; developmental skeletal abnormalities; and malignancies such as multiple myeloma and breast cancer, negatively affect the skeleton. There is an ongoing need to better understand the causes of these diseases to support the development of more effective and well- tolerated therapies. Comprehensive analyses of the molecular changes that contribute to these conditions may lead to the development of such therapies.