Promoting DMSC-mediated craniofacial regeneration by estrogen

描述（由申请人提供）：本次K08职业奖的总体目标是制定和执行职业发展计划，使Christine Hong博士能够投入更多时间研究她的职业道路，从而使她成为颅面疾病及其治疗相关转化研究的独立研究者。在王存宇博士的建议指导下，建立了一个全面的计划和跨学科咨询委员会，在基础和临床前研究方面进行高效和全面的培训，并通过以下研究项目制定了科学成果的路线图。使用间充质干细胞（MSCs），包括牙间充质干细胞（DMSCs）进行细胞介导治疗，对骨和颅面疾病具有很大的前景，因为MSCs容易获得，并表现出分化为功能不同的谱系的潜力，包括骨形成细胞（成骨细胞）和脂肪细胞（脂肪细胞）。我们对骨髓间充质干细胞（BMSCs）和骨髓间充质干细胞的初步研究表明，雌激素（17β-雌二醇（E2））显著增加成骨潜能。此外，E2选择性诱导KDM4B的表达，KDM4B是一种负责去除沉默标记H3K9me3的组蛋白去甲基化酶。为此，我们假设雌激素是一种合成代谢剂，通过表观遗传调节成骨基因（如DLX5和HOXC6）来增强DMSCs的成骨分化，从而促进DMSCs介导的颅面再生治疗。这一假设将通过以下具体目的进行验证：1)确定雌激素受体在雌激素诱导的DMSCs成骨分化中的作用；2)确定KDM4B在雌激素诱导的DMSC分化中调控成骨基因的功能作用；3)采用小鼠模型研究雌激素在DMSCs介导的颅面骨缺损再生中的作用。鉴于颅面和其他骨缺损的普遍存在，确定分子途径并使用动物模型验证以更好地调节骨再生至关重要。通过阐明雌激素介导的成骨机制，以及雌激素和间充质干细胞在临床前水平的联合治疗模式，本研究的完成将为未来的创新奠定基础

DESCRIPTION (provided by applicant): 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,17β-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.