MECHANISM OF MATRIX VESICLE BIOGENESIS

基质囊泡生物发生机制

• 批准号: 6044765
• 负责人: ELLIS E GOLUB
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044765
• 关键词: apoptosis; calcium; chick embryo; chondrocytes; extracellular matrix; membrane lipids; normal ossification; osteoblasts; osteogenesis; vesicle /vacuole

DESCRIPTION (adapted from the Investigator's abstract): Vertebrate biomineralization begins when Matrix vesicles (MV) are budded from the plasma membrane of osteoblasts and chondrocytes prior to the onset of matrix mineralization in cartilage and bone. MV contain a specific subset of the protein and lipid constituents of the parent cell plasma membrane, and are believed to initiate matrix calcification. The mechanisms which carry out and control MV biogenesis are not currently understood. The experiments described in this application are aimed at providing crucial new information in this important and thus far under studied area. The principle goal of this proposal is to test four hypotheses of MV formation: 1. MV arise as a consequence chondrocyte apoptosis, 2. MV bud from plasma membranes as the result of overexpression of MV proteins, 3. MV form in response to a rise in [Ca2+]I and 4. Cells bud off MV as the result of specific changes in membrane lipid composition. The investigators propose to test these hypotheses against two gold-standard criteria for authentic MV: 1. Do vesicles formed by each of the hypothetical mechanisms contain the same protein and lipid constituents as tissue-derived MV, and 2. How well can these vesicles initiate mineralization. They will also ascertain the spacial and temporal occurrence of each of the hypothetical mechanisms in developing mineralized tissues, and relate this pattern to the emergence of MV in the tissue. To achieve these goals and test these hypotheses, they propose the following specific aims: to determine whether vesicles formed during chondrocyte apoptosis are MV, to ascertain whether overexpression of MV proteins can initiate MV formation, to determine how modulation of intracellular calcium regulates MV formation in osteoblasts and chondrocytes, to determine whether MV formation is driven by specific changes in plasma membrane lipid composition. The successful completion of this work will advance our knowledge of the regulation of hard tissue formation. This information is crucial for developing new approaches to metabolic bone diseases such as Pagets's disease of bone and osteoporosis, and may also contribute to novel therapies for the repair of craniofacial defects and fracture.

描述（改编自研究者摘要）：脊椎动物 当基质囊泡（MV）从血浆中出芽时，生物矿化开始 成骨细胞和软骨细胞的膜在基质出现之前 软骨和骨中的矿化。MV包含一个特定的子集， 蛋白质和脂质成分的母细胞质膜，并 被认为是引起基质钙化的原因。执行和 控制MV生物发生目前还不清楚。描述的实验 旨在提供关键的新信息， 这是一个重要的，迄今尚未研究的领域。本提案的主要目标是 是为了测试MV形成的四个假设：1。因此，MV出现 软骨细胞凋亡; 2. MV芽从质膜作为结果 MV蛋白的过表达，3. MV形式响应于[Ca 2 +]I的升高， 4.由于膜脂的特殊变化，细胞从MV中出芽 混合物.研究人员建议用两种方法来检验这些假设。 真实MV的黄金标准：1.每一个细胞形成的囊泡 假设的机制包含相同的蛋白质和脂质成分， 组织来源的MV，和2.这些囊泡如何启动矿化。 他们还将确定每一个事件的空间和时间发生情况， 假设的机制，在发展矿化组织，并与此相关， 在组织中出现MV的模式。为了实现这些目标， 这些假设，他们提出了以下具体目标： 软骨细胞凋亡过程中形成的囊泡是否为MV，以确定 MV蛋白的过表达是否可以启动MV形成，以确定 成骨细胞内钙离子的调节如何调节MV的形成 和软骨细胞，以确定MV的形成是否是由特定的 质膜脂质组成的变化。成功完成本 这项工作将促进我们对硬组织形成的调节的认识。 这些信息对于开发新的代谢骨方法至关重要 疾病如佩吉特氏骨病和骨质疏松症，并且还可以 有助于修复颅面缺损的新疗法， 骨折