Defining Novel Cellular Circuitry and Communication in Fibrous Dysplasia
Abstract
Fibrous dysplasia (FD) is a severe skeletal disease where benign tumors cause bone deformities, fractures, and pain. This disease is caused by mutations in some cells in a protein called Galphas that changes levels of a signaling molecule called cyclic AMP. While it is known that high cyclic AMP levels cause problems in FD, exactly how this occurs remains poorly understood. In addition, we do not fully understand how bone becomes weak in FD with resultant fractures and bone pain. These knowledge gaps have hampered efforts of therapeutic development to treat FD patients or improve their health conditions. Here, we will study how high cyclic AMP levels cause disease in bone cells with FD lesions. We will use multiple, complementary approaches to better understand how downstream changes within cells in the cyclic AMP pathway drives fibrous dysplasia through molecular changes within bone cells bearing Galphas mutations. In addition, FD is a mosaic genetic disease where some cells bear the mutation, while many other cells do not. Mutation-bearing cells cause dramatic changes in nearby normal cells that do not bear FD mutations. We will study how normal and abnormal cells talk to one another using a novel approach to study inter-cellular communication. This work will identify new mechanisms through which rare mutation-bearing cells cause dramatic problems throughout the skeleton. Finally, we will test new therapeutic approaches in cutting-edge mouse FD models and confirm our discoveries in human samples from FD patients. The new information and treatment strategies developed here will benefit military personnel with FD and other related bone problems like bone pain, stress fractures, heterotopic ossification, and poor fracture healing.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310349
Entities
People
- Yingzi Yang
Organizations
- Harvard University
- United States Army