MECHANISM OF MATRIX VESICLE BIOGENESIS

基质囊泡生物发生机制

• 批准号: 6498083
• 负责人: ELLIS E GOLUB
• 金额: $ 27.77万
• 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/6498083
• 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（改编自研究者的摘要）：脊椎动物 当基质囊泡 (MV) 从血浆中出芽时，生物矿化开始 基质出现之前的成骨细胞和软骨细胞膜 软骨和骨的矿化。 MV 包含特定子集 母细胞质膜的蛋白质和脂质成分，并且是 据信会引发基质钙化。执行和执行的机制 目前尚不清楚控制 MV 生物发生。所描述的实验 本申请旨在提供这方面的重要新信息 重要且迄今为止仍在研究的领域。本提案的主要目标 是检验 MV 形成的四个假设： 1. MV 作为结果出现 软骨细胞凋亡，2. 质膜上的 MV 芽是由于 MV 蛋白过度表达，3. MV 形式响应 [Ca2+]I 和 4. 由于膜脂的特定变化，细胞出芽了 MV 作品。研究人员建议用两种方法来测试这些假设 真实 MV 的黄金标准： 1. 是否存在由每个 MV 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，以及 2. 这些囊泡启动矿化的能力如何。 他们还将确定每个事件的空间和时间发生情况 发育矿化组织的假设机制，并将其联系起来 组织中 MV 出现的模式。为了实现这些目标并进行测试 根据这些假设，他们提出了以下具体目标：确定 软骨细胞凋亡过程中形成的囊泡是否为MV，以确定 MV 蛋白的过度表达是否可以启动 MV 形成，以确定 细胞内钙的调节如何调节成骨细胞中 MV 的形成 和软骨细胞，以确定 MV 形成是否由特定的驱动 质膜脂质成分的变化。本次活动的顺利完成 这项工作将增进我们对硬组织形成调节的了解。 这些信息对于开发代谢骨的新方法至关重要 佩吉茨骨病和骨质疏松症等疾病，也可能 为修复颅面缺陷的新疗法做出贡献 断裂。