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MATRIX VESICLE MEDIATED MATRIX CALCIFICATION

基质囊泡介导的基质钙化

基本信息

批准号：
8069228
负责人：
ELLIS E GOLUB
金额：
$ 31.64万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-20 至 2013-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The role of matrix vesicles (MV) in hard tissue mineralization has been debated since these enigmatic particles were first observed more than 40 years ago in the matrix of calcifying cartilage. In those studies, and many more recent investigations, it has been shown that MV are present in the matrix of many mineralizing tissues, including cartilage, bone and dentin, and that they are often seen as the site where mineral crystals first form. When these tissues mineralize, however, the vast majority of the mineral is found associated with collagen fibrils, which are completely permeated and encased in mineral. A key question in the proposed mechanism of MV initiated matrix mineralization is to explain how mineral crystals formed within MV initiate collagen calcification. This is the problem at which this proposal is aimed. To answer this question, we propose three hypothetical models which each provide a possible answer to the question. The first model focuses on the role of MV enzymes in altering the relative concentration of inorganic phosphate (Pi) and inorganic pyrophosphate (PPi) to make the extracellular milieu permissive for mineral to nucleate on matriix molecules directly. The second model predicts that MV nucleate mineral internally, release small crystals and that these crystals seed the mineralization of the matrix. The third model specificies that MV bind to collagen fibrils at specific sites, and that while bound, they facilitate crystal entry into the colagen fibrils. Three Specific Aims are proposed to test these models and distinguish amongst them. The first experiments are designed to decide whether MV must come into proximity with collagen fibrils to correctly mineralize them. If proximity is required, then the first model in unlikely to be correct. The next experiments will examine the proposition that MV binding is necessary for collagen mineralization. These experiment will allow us to distinguish between the 2nd and 3rd models. Another set of experiments will examine the possibility that MV associated enzymes remodel the collagen fibrils to facilitate crystal entry. Depending on whether the remodeling enzymes are MV associated or are free in the matrix, these data will support either model 2 or model 3. Finally, we will construct synthetic models of MV, and test the function of MV proteins and lipids in isolation and together to better distinguish among the proposed hypotheses. When these experiments are completed, our knowledge of how MV initiate matrix calcification will be greatly enhanced.

描述(申请人提供)：自从40多年前在钙化软骨基质中首次发现这些神秘的颗粒以来，基质小泡(MV)在硬组织矿化中的作用一直存在争议。在这些研究中，以及最近的许多研究中，已经表明MV存在于许多矿化组织的基质中，包括软骨、骨和牙本质，它们通常被视为矿物晶体最早形成的地方。然而，当这些组织矿化时，绝大多数矿物质与胶原蛋白纤维有关，胶原蛋白纤维完全渗透并包裹在矿物质中。在提出的MV引发基质矿化的机制中，一个关键问题是解释MV中形成的矿物晶体如何引发胶原钙化。这就是这项建议旨在解决的问题。为了回答这个问题，我们提出了三个假设模型，每个模型都提供了这个问题的可能答案。第一个模型着重于MV酶在改变无机磷(PI)和无机焦磷(PPI)的相对浓度中的作用，使细胞外环境允许矿物质直接在基质分子上成核。第二种模型预测MV在内部成核矿物，释放小晶体，这些晶体为基质的矿化提供种子。第三种模型规定MV在特定的位置与胶原纤维结合，当结合时，它们促进晶体进入胶原纤维。提出了三个具体目标来检验这些模型并区分它们。最初的实验旨在确定MV是否必须接近胶原纤维才能正确地矿化它们。如果需要接近，那么第一个模型不太可能是正确的。接下来的实验将检验MV结合对于胶原矿化是必要的这一命题。这些实验将使我们能够区分第二和第三种型号。另一组实验将检验MV相关酶重塑胶原纤维以促进晶体进入的可能性。根据重塑酶是MV相关的还是在基质中是游离的，这些数据将支持模型2或模型3。最后，我们将构建MV的合成模型，并单独和一起测试MV蛋白质和脂类的功能，以更好地区分提出的假说。当这些实验完成后，我们对MV如何启动基质钙化的了解将大大增强。