Promoting DMSC-mediated craniofacial regeneration by estrogen

描述（由申请人提供）：K 08职业奖的总体目标是制定和执行职业发展计划，这将使克莉丝汀洪博士有更多的时间致力于研究她的职业道路，使她成为一名独立的研究者，从事与颅面疾病及其治疗相关的转化研究。在王存玉博士和跨学科咨询委员会的建议指导下，制定了一项全面的计划，以便在基础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制定了科学成就的路线图。使用间充质干细胞（MSC）（包括牙科MSC（DMSC））的细胞介导的疗法对于骨和颅面病症具有很大的希望，因为MSC容易获得并且表现出分化成功能不同的谱系（包括骨形成细胞（成骨细胞）和脂肪细胞（脂肪细胞））的潜力。我们使用骨髓间充质干细胞（BMSCs）和DMSCs的初步工作表明，雌激素，17β-雌二醇（E2），显着增加成骨潜能。此外，E2选择性诱导KDM 4 B的表达，KDM 4 B是一种负责去除沉默标记H3 K9 me 3的组蛋白去甲基化酶。为此，我们假设雌激素是DMSC介导的颅面再生治疗中的合成代谢剂，其通过成骨基因的表观遗传调节（例如，DLX 5和HOXC 6）。该假设将通过以下具体目的进行检验：1）确定雌激素受体参与雌激素诱导的DMSC成骨分化; 2）确定KDM 4 B在雌激素诱导的DMSC分化中调节成骨基因的功能作用;和3）使用小鼠模型研究雌激素在DMSC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广泛流行，识别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MSC在临床前水平的组合治疗模式，完成当前提案将作为未来努力改进创新的基础， 颅面组织工程总结：目前的K 08提案旨在通过借鉴我的学术，临床和研究经验，并利用加州大学洛杉矶分校健康科学校园的大量资源，促进我的科学独立性的实现，同时由一个跨学科咨询委员会仔细指导，该委员会由世界知名科学家组成，在高度相关的专业领域。

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.