Hes1基因调控骨细胞成熟在骨改建中的作用及与雌激素缺乏的骨质疏松症的相关性研究

骨细胞在调控骨改建过程中扮演核心角色，但申请者发现，成骨细胞HIF-1α通路失活后的骨组织、以及雌激素缺乏的骨组织，其骨改建过程“失衡”现象都与骨细胞生物学特性转化有关。本课题基于既有的研究线索，在国自然青年项目的基础上，提出”骨细胞通过成熟演化过程参与调控骨改建“的假说；并以可诱导的、成骨细胞Hes1基因条件敲除和过表达小鼠模型及与之相对应的细胞模型为研究对象，深入了解Hes1通路调控成骨细胞向骨细胞演化、骨细胞时空分布特征和表型表达的关键环节及其与骨改建过程间的关系；揭示激活Hes1后骨细胞对破骨细胞生成和分化的调节作用及其所涉及的细胞分子生物学事件；并阐明Hes1是否参与介导雌激素缺乏后的骨改建”失衡“事件。这不仅有助于加深或更新骨塑建/骨改建过程的认识，而且有望发现与确定新的调控因子或分子靶点，为提出促进骨修复、防治代谢性骨病的新举措储备科学基础。

osteocyte plays a central role in bone remodeling, but we found that the imbalanced bone remodeling after the inactivation of osteoblastic HIF-1α pathway and estrogen-deficiency are both related to osteocytogenesis process. Based on the results, we hypothesized that "the osteocyte participate in the regulation of bone remodeling through osteocytogenesis”. With inducible mouse model of osteoblastic conditional Hes1 knockout and overexpression mice and related cell line, we try to understand the key links of Hes1 pathway in regulating osteocytogenesis and to reveal the Hes1 overexpression in osteocytes in regulating osteoclast formation and the cellular molecular biological events involved; and to clarify whether Hes1 is involved in the estrogen deficiency-induced bone remodeling imbalance. This will not only help to deepen or renew the understanding of the bone remodeling, but also to discover and determine new factors or molecular targets in bone remodeling, and to reserve a scientific support for bone repair and osteoporosis treatment.