损伤诱导的、骨形态发生蛋白依赖的异位成骨性间充质干细胞龛在异位骨化中的机理研究

Heterotopic ossification (HO) is bona fida bone formation outside of the normal skeletal system. HO can either be a costly acquired complication of traumatic injuries or a rare, severely disabling inherited condition, such as Fibrodysplasia Ossificans Progressiva (FOP), which is caused by gain-of-function mutations of a BMP type I receptor (ACVR1). The exact underlying molecular and cellular mechanisms of FOP are still far from clear. We have established a unique transgenic mouse model (Nse-BMP4) for the first time, which recapitulated not only recapitulated all the characteristic features of FOP, but also the major hallmarks of acquired HO. Our previous data also demonstrated the involvement of multiple factors in HO that importantly are not usually associated with normal bone formation, including substance P (SP) from the peripheral nervous system, cells of the immune system (mast cells & macrophages), non-inherited triggers (injuries) and unique subpopulations of mesenchymal stem cells (MSCs). Based on these findings, in this proposal, we hypothesize that multiple disease specific contributing factors, including both cellular and extracellular molecular elements, co-ordinate to form a unique local, hierarchical microenvironment that works as a dynamic functional unit to induce and propagate HO. The concept of induced microenvironmental niches is completely consistent with our long-term observations and explains all available data in the literatures. In contrast, no alternative hypothesis can do so in a single model. Furthermore, the niche concept provides a framework that allows testing the functional consequence of individual contributing factors in their own native microenvironmental context. More importantly, this should also facilitate design of a therapy for the disorder, the important goal of this project, and one specific suggestion of this new concept is to target the niche instead of individual factors. In addition to the specific impact on the understanding of the pathophysiology of HO, the proposed studies may provide valuable insights into several related fields. For example, mature HO niches contain not only bone forming MSCs but also hematopoietic stem cells (HSCs) within bone marrow. Therefore the mature HO niche is a unique model to study both HSCs and MSCs, and their inter-regulation. The proposed study may deepen our understanding of the regulation of MSC populations which, in turn, should also benefit the understanding of normal, orthotopic bone remodeling and regeneration, because these normal processes are at least partially regulated by the activities of endogenous MSCs. The proposed studies and our animal models may also be useful in the evaluation for regenerative medicine of new osteoinductive biomaterials and growth factors. We believe that our proposed study is not only of great potential interests for multiple interdisciplinary fields, but also has direct clinical implications.

异位骨化（HO）是指在正常骨骼系统之外的真正成骨。获得性HO较常见，通常由神经系统或手术创伤（如骨关节置换手术）引起。FOP虽罕见，但因其直接牵涉到BMP这一至关重要的信号传导途径，且症状特别严重，因而国外对这方面的研究非常重视。但国内相关研究相当有限且重点不突出。目前亟待解决的关键问题是阐明HO的发病机理，这样才可能有效防治该该病，但目前没有一个理论能解释所有的临床和实验数据。本课题组曾在世界上首先建立FOP及HO的小鼠模型，并证明多种通常不参与正常骨形成的因素（包括肥大细胞、巨噬细胞、炎性因子等）参与HO的发生、发展。本课题提出一新假说：即多种疾病特异的因素通过参与和促进异位成骨性间充质干细胞龛的形成和扩展来实现这一病理过程。从分子、细胞、和整体动物水平，透过跨学科手段验证这一假说，且尝试在该假说指导下的新治疗策略将不但对HO 本身，而且将对多个相关的交叉学科有深远的理论和现实意义。

本课题提出一新假说：即多种疾病特异的因素通过参与和促进异位成骨性间充质干细胞龛的形成和扩展来实现这一病理过程。为验证该假说，我们从分子、细胞、和整体动物水平，透过跨学科手段进行研究验证，该研究将对多个相关的交叉学科有深远的理论和现实意义。总体来讲，该课题的深入研究基本证实了当初的假说，取得了阶段性成果。在这些研究的基础之上，课题组以第一作者/联系作者发表了多篇论文（包括SCI论文，代表性SCI论文首页见附件），以及多篇英文专著。从研究成果来看，课题完成情况良好。但美中不足的是，课题研究过程中遭受包括天灾和人祸双重干扰（详情见正文），因此有些些预期实验无法按时完成。作为课题主持人，我感到非常遗憾。考虑到课题剩余部分没有完成，剩余基金还相对较多，真心希望基金委同仁和领导能够考虑给该课题延期一年来完成剩余的实验。

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