Overview
The Center for Musculoskeletal Disease Research is a Center of Biomedical Research Excellence (COBRE) at UAMS funded by the National Institute of General Medical Sciences (NIGMS). The CMDR is a multidisciplinary center that encompasses a broad area of musculoskeletal research, including osteoporosis, orthopedics, biomechanics, multiple myeloma, and cancer metastases to bone, osteoarthritis, osteomyelitis, and aberrant skeletal development. The long-range goal of the Center is to establish the scientific foundation for sustained excellence in musculoskeletal research in central Arkansas. One important component of this effort is to fund pilot projects as a means of supporting the efforts of musculoskeletal investigators to pursue extramural funding. More information on how the CMDR is structured, our core facilities, and services can be obtained on our website or by contacting the CMDR Director, Dr. Charles O’Brien at caobrien@uams.edu.
Projects
Amy Yoshiko Sato, Ph.D.
Assistant Professor, Physiology and Cell Biology
Title of the project: Targeting proteolysis and Sclerostin atrophy signaling in Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) is caused by loss-of-function mutations in the dystrophin gene that lead to an impairment in both muscle and bone, resulting in high fracture rates. The current standard of care for DMD is chronic administration of glucocorticoids, which initially slow the disease. However, because of the direct negative effects of glucocorticoids on muscle and bone cells, chronic treatment of DMD patients with glucocorticoids leads to even lower bone mineral density than untreated patients. Thus, there is a need to identify new therapeutic targets to improve clinical outcomes in DMD. Currently, the exact cellular and molecular mechanisms underlying pathologic bone loss in DMD and the impact of glucocorticoids on bone cell populations in DMD remain unclear. The overall goal of this project is to investigate the hypothesis that targeting proteolytic atrophy signals will preserve muscle and bone in DMD. We anticipate that the successful completion of the proposed studies will advance knowledge of the effects of glucocorticoids on DMD and guide the development of new therapeutic approaches to improve outcomes in patients with muscular dystrophy.
Intawat Nookaew, Ph.D.
Associate Professor, Biomedical Informatics
Title of the project: Role of Extrachromosomal Circular DNA in Bone
Extrachromosomal circular DNA (eccDNA) is a closed-circular DNA derived and free from chromosomes. EccDNAs are formed as a product of chromosomal operations, ubiquitously expressed, vary in length from 50 to over 100k bp, and are present in both normal and cancer cells. EccDNAs harbor full-length/truncated transcripts, enhancers, or small RNAs, which regulate chromatin accessibility and gene expression. Growing evidence indicates eccDNAs have important roles in aging, cancer progression, and muscle function. However, the functional relevance of eccDNAs in the bone microenvironment remains to be elucidated. In this pilot study we aim to identify eccDNAs production by bone cells and examine their contribution and regulation of bone microenvironment. We anticipate that the successful completion of the proposed study will provide unprecedented insights into the molecular roles of eccDNAs in bone and a deeper understanding of the molecular mechanisms underlying bone remodeling by eccDNAs.