Determining the Role of Brain-Derived CCN3 in Bone and Marrow Fat Metabolism

ABSTRACT/PROJECT SUMMARY This application presents a five-year mentored research and training plan that will prepare Dr. Muriel Babey to be a leader in the field of the skeletal, aging, and metabolic physiology. Dr. Babey completed her MD at the University of Berne, Switzerland and her clinical fellowship of Endocrinology, Metabolism and Diabetes at the University of California, San Francisco (UCSF). She is an Assistant Adjunct Professor in Endocrinology and Diabetes at UCSF and supported by an NIDDK supplement for emerging physician-scientist under the mentorship of Dr. Holly Ingraham. Dr. Babey’s long-term career goal is to unravel the fundamental mechanisms governing the intricate interplay between skeletal, aging, and metabolic physiology. This project will facilitate foundational discoveries for her independent research program, as she seeks to delineate the role of brain- derived cellular communication network factor 3 (CCN3) in bone and marrow fat metabolism. Based on multiple assays, CCN3 emerged as the most promising pro-osteogenic factor from KISS1 neurons of the arcuate nucleus (ARCKISS1). The proposal builds on this recent discovery (11) and will further test the hypothesis that CCN3 drives bone formation and reduces bone marrow fat. Using in vitro and in vivo models, she proposes to 1) determine how the dose and levels of circulating brain-derived CCN3 affect bone formation in vitro and in vivo assays and 2) determine the role of circulating CCN3 on bone and marrow fat metabolism during aging, menopause and after a HFD dietary challenge. This work will provide strong evidence for further development and future clinical trials of CCN3, ultimately providing a novel therapeutic approach for mitigating osteoporosis and fracture risk. The proposed career development plan includes training in brain stereotaxic surgery, skeletal stem cell biology and osteocyte mediated perilacunar remodeling. Dr. Babey will learn all the skills needed for an independent research career, including supervising trainees and staff, grant writing and scientific communication. She has assembled a world-class mentorship team with complementary expertise in brain-body communicationin female physiology (Primary mentor, Dr. Holly Ingraham), skeletal stem cell biology (Co-Mentor, Dr. Thomas Ambrosi), osteocyte mediated perilacunar remodeling and mechanobiology (Co-Mentor, Dr. Tamara Alliston), novel therapeutic approach for human skeletal disorders and bone injuries (Advisor, Dr. Edward Hsiao), link basic mechanism of metabolic regulation to causality in clinical patients (Advisor, Dr. Suneil Koliwad) and bone marrow adipose tissue and bone crosstalk with nerves (Advisor, Dr. Erica Scheller). Dr. Babey, her mentors, and the Department of Medicine at UCSF are fully committedto this proposal and to her goal of becoming an independent physician-scientist by the completion of this training period.