Promoting DMSC-mediated craniofacial regeneration by estrogen

描述(申请人提供)：K08职业发展奖的总体目标是制定和执行职业发展计划，让Christine Hong博士有更多的时间研究她的职业道路，使她成为与颅面部疾病及其治疗相关的翻译研究的独立研究员。在王存玉博士和一个跨学科咨询委员会的建议指导下，建立了一个全面的计划，以便在基础研究和临床前研究方面进行有效和全面的培训，并通过以下研究项目为科学成就制定路线图。使用包括牙科间充质干细胞(DMSCs)在内的间充质干细胞(MSCs)进行细胞介导的治疗在骨和颅面疾病中具有很大的前景，因为MSCs很容易获得，并显示出分化为不同功能谱系的潜力，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和骨髓间充质干细胞的初步研究表明，雌激素17-雌二醇(17β-estadiol，E_2)显著增强成骨潜能。此外，E2选择性地诱导KDM4B的表达，KDM4B是一种负责去除沉默标记H3K9me3的组蛋白去甲基酶。为此，我们假设雌激素通过对成骨基因(如DLX5和HOXC6)的表观遗传调节来促进DMSCs的成骨分化，从而在DMSc介导的颅面再生治疗中是一种合成代谢因子。这一假说将通过以下具体目标得到验证：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；以及3)利用小鼠模型研究雌激素在DMSCs介导的颅面部骨缺损再生中的作用。鉴于颅面部和其他骨缺陷的普遍存在，识别分子途径并使用动物模型验证以更好地调控骨再生是至关重要的。通过在临床前水平阐明雌激素介导的成骨机制以及雌激素和骨髓间充质干细胞的联合治疗模式，目前的建议的完成将为未来努力的改进创新奠定基础。 颅面组织工程。摘要：目前的K08建议是通过利用我的学术、临床和研究经验，并利用加州大学洛杉矶分校健康科学园区的大量资源，同时在一个由高度相关专业领域的世界知名科学家组成的跨学科咨询委员会的精心指导下，制定的，以促进我实现科学独立。

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.