The overall objective of this K08 career award is to formulate and execute career development plans which will allow Dr. Christine Hong to dedicate more time to research on her career pathway, leading to her establishment as an independent investigator in translational research related to craniofacial disorders and their treatment. A comprehensive plan was constructed under the proposed mentorship of Dr. Cun-Yu Wang and a trans-disciplinary advisory committee for efficient and comprehensive training in both basic and preclinical research, with a roadmap for scientific achievement through the following research project. Cell- mediated therapy using mesenchymal stem cells (MSCs) including dental MSCs (DMSCs) holds great promise for bone and craniofacial disorders as MSCs are readily available and exhibit the potential to differentiate into functionally distinct lineages including bone forming cells (osteoblasts) and fat cells (adipocytes). Our preliminary work using both bone marrow mesenchymal stem cells (BMSCs) and DMSCs indicated that estrogen,17?-estradiol (E2), increased osteogenic potential significantly. Furthermore, E2 selectively induced expression of KDM4B, a histone demethylase responsible for removing the silencing mark, H3K9me3. To this end, we hypothesize that estrogen is an anabolic agent in DMSC-mediated craniofacial regeneration therapy by enhancing osteogenic differentiation of DMSCs through epigenetic modulation of osteogenic genes (e.g., DLX5 and HOXC6). This hypothesis will be tested by the following specific aims: 1) to determine the involvement of estrogen receptors in estrogen-induced osteogenic differentiation in DMSCs;2) to determine the functional role of KDM4B in regulating osteogenic genes in estrogen-induced DMSC differentiation;and 3) to investigate the role of estrogen in regeneration of craniofacial bone defect mediated by DMSCs using a mouse model. Given the widespread prevalence of craniofacial and other bony defects, it is critical to identify molecular pathways and validate using animal models to better regulate bone regeneration. By elucidating the mechanistic insights of estrogen-mediated osteogenesis and combinatorial therapeutic modes of estrogen and MSCs at the preclinical level, completion of the current proposal will serve as the foundation for improved innovations for future efforts in craniofacial tissue engineering. Summary: The current K08 proposal is formulated to facilitate achievement of my scientific independence by drawing upon my academic, clinical and research experiences, and utilizing the vast resources of the UCLA Health Sciences campus, all while carefully guided throughout by a trans-disciplinary advisory committee comprised of world renowned scientists in highly relevant fields of expertise.
Given the widespread prevalence of craniofacial and other bony defects, it is critical to identify molecular pathways and validate using animal models to enhance therapeutic agents for bone regeneration. Estrogen (E2) is a naturally occurring steroid that plays critical roles in bone homeostasis. Novel anabolic therapies for craniofacial defects, such as the local delivery of estrogen along with MSCs that could be developed upon validation by the proposed study, could present ground-breaking means to significantly enhance bone formation while minimizing the undesired effects of existing treatments.