MECHANISM OF MATRIX VESICLE BIOGENESIS

基质囊泡生物发生机制

• 批准号: 6708398
• 负责人: ELLIS E GOLUB
• 金额: $ 29.45万
• 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 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6708398
• 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《调查者摘要》)：脊椎动物 当基质小泡(MV)从血浆中萌发时，生物矿化就开始了 基质形成前的成骨细胞和软骨细胞膜 软骨和骨骼中的矿化。MV包含特定的子集 亲本细胞质膜的蛋白质和脂肪成分，以及 据信会引发基质钙化。执行和执行的机制 对照MV的生物发生目前还不清楚。所描述的实验 目的是在本申请中提供关键的新信息 这是一个重要的领域，也是目前正在研究的领域。这项提案的主要目标是 是检验关于MV形成的四个假说：1.MV由此产生 软骨细胞凋亡，2.MV从质膜上萌发的结果 MV蛋白的过度表达，3.对[Ca~(2+)]i和[Ca~(2+)]i升高的反应形成MV 4.由于膜脂的特殊变化，细胞萌发了MV 组成。研究人员建议针对两个假设来检验这些假设 真实性MV的金标准：1.每一个人形成的水泡 假设的机制包含相同的蛋白质和脂肪成分 组织来源的MV；2.这些小泡启动矿化的程度。 他们还将确定每个事件的时空发生情况 矿化组织形成的假想机制，并与此相关 病毒在组织中出现的模式。要实现这些目标并测试 这些假设提出了以下具体目标：确定 软骨细胞凋亡过程中形成的小泡是否为MV，以确定 MV蛋白的过表达是否能启动MV的形成，以确定 细胞内钙离子调控成骨细胞MV形成的机制 和软骨细胞，以确定MV的形成是否由特定的 质膜脂组成的变化。成功地完成这项工作 这项工作将促进我们对硬组织形成规律的了解。 这一信息对于开发新陈代谢骨骼的新方法至关重要。 疾病，如Pagets病和骨质疏松症，也可以 为修复颅面和面部缺陷贡献新的疗法 骨折。