Dynamics of Raft Formation and Growth

筏形成和生长的动力学

基本信息

  • 批准号:
    7581585
  • 负责人:
  • 金额:
    $ 29.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-01-01 至 2012-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Membrane proteins that are critical for cell signaling and other biological processes reside in rafts, but rafts have been difficult to study because they have submicroscopic sizes, dynamic structures, and components that do not have fixed stoichiometries. The compositions of rafts - proteins and lipids - must be determined in order to understand which proteins interacting in cellular cascades come into proximity with each other as a result of their residence in a raft. A new experimental procedure now allows cellular rafts to be isolated at the physiological temperature of 370C, rather than the previously necessary temperature of 40C, enabling basic question in raft studies to be addressed. The compositions of many domains that exist within a cell membrane at mammalian body temperature (370C) are likely to be different from those of cell membranes that are kept on ice (40C), so many domains cannot be reliably determined at low temperature. The composition of rafts at biological temperature can now be determined, and membrane anchors of proteins favored in rafts can be compared to data derived at 40C. The relationship between types of proteins (GPI-anchored, transmembrane domain, prenylated) and amounts of cholesterol in a raft will be classified. Comparison of cholesterol levels in different types of rafts will uncover mechanisms that cause cholesterol to move between rafts. The displacement of one protein by another inside a raft, and the resulting effect on cellular processes, if any, will be assessed. The physical chemistry that controls the relationship between cholesterol and sphingomyelin content will be studied in a model raft system. The model system also allows the experimentally elusive question of how proteins contribute to raft formation to be approached in a concrete manner. For cellular studies, a new method will be employed that exploits the fact that the pressure needed to rupture a vesicle depends directly on the lipid composition of its membrane. Combining this method with the traditional approach of separation by membrane density will allow collection of a large range of domains. This will provide, for the first time, analysis of protein and lipid raft content without alteration caused by low temperature, detergents, and/or alkaline pH required by all previous raft isolation procedures. Isolating model bilayer domains containing a peptide and measuring compositions will determine the physical mechanisms that create these domains. This will yield experimentally testable hypotheses of mechanisms of biological domain formation. PUBLIC HEALTH RELEVANCE: Cholesterol is the most abundant molecule in cell plasma membranes, and its distribution within rafts and other domains is critical to the location of proteins within membranes. High cholesterol levels are implicated in diseases, including atherosclerosis and strokes. Improper distribution of proteins within rafts and other domains of cell membranes alters cell growth, related to cancers. Thus, determining the relationship between proteins and lipids, including cholesterol, within membrane rafts bears directly on cell function in health and disease.
描述(由申请人提供):对细胞信号传导和其他生物过程至关重要的膜蛋白存在于筏中,但筏一直难以研究,因为它们具有亚微观尺寸,动态结构和不具有固定化学计量的组分。筏的组成-蛋白质和脂质-必须确定,以了解哪些蛋白质在细胞级联中相互作用,由于它们在筏中的居住而彼此接近。现在,一种新的实验程序允许在370 ℃的生理温度下分离细胞筏,而不是以前所需的40 ℃温度,使筏研究中的基本问题得到解决。在哺乳动物体温(370 ℃)下存在于细胞膜内的许多结构域的组成可能与保持在冰上(40 ℃)的细胞膜的组成不同,因此许多结构域不能在低温下可靠地测定。现在可以确定生物温度下筏的组成,筏中有利的蛋白质的膜锚可以与40 ℃下获得的数据进行比较。蛋白质类型(GPI锚定,跨膜结构域,异戊烯化)和筏中胆固醇量之间的关系将被分类。比较不同类型的筏中的胆固醇水平将揭示导致胆固醇在筏之间移动的机制。将评估筏内一种蛋白质被另一种蛋白质取代的情况,以及对细胞过程的影响(如果有的话)。控制胆固醇和鞘磷脂含量之间关系的物理化学将在模型筏系统中进行研究。该模型系统还允许蛋白质如何有助于筏形成的实验难以捉摸的问题,以具体的方式接近。对于细胞研究,将采用一种新的方法,该方法利用了使囊泡破裂所需的压力直接取决于其膜的脂质组成的事实。将该方法与通过膜密度分离的传统方法相结合将允许收集大范围的域。这将首次提供蛋白质和脂质筏含量的分析,而不会因所有先前筏分离程序所需的低温、洗涤剂和/或碱性pH值而发生变化。分离含有肽的模型双层结构域并测量组合物将确定产生这些结构域的物理机制。这将产生实验验证的假说的机制,生物领域的形成。公共卫生关系:胆固醇是细胞质膜中最丰富的分子,其在筏和其他结构域中的分布对于蛋白质在膜内的定位至关重要。高胆固醇水平与包括动脉粥样硬化和中风在内的疾病有关。蛋白质在细胞膜的筏和其他结构域中的不适当分布会改变细胞生长,与癌症有关。因此,确定膜筏内蛋白质和脂质(包括胆固醇)之间的关系直接关系到健康和疾病中的细胞功能。

项目成果

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FREDRIC S COHEN其他文献

FREDRIC S COHEN的其他文献

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{{ truncateString('FREDRIC S COHEN', 18)}}的其他基金

Biophysical Mechanisms of Cholesterol Homeostasis
胆固醇稳态的生物物理机制
  • 批准号:
    10454109
  • 财政年份:
    2021
  • 资助金额:
    $ 29.1万
  • 项目类别:
Biophysical Mechanisms of Cholesterol Homeostasis
胆固醇稳态的生物物理机制
  • 批准号:
    10624260
  • 财政年份:
    2021
  • 资助金额:
    $ 29.1万
  • 项目类别:
Biophysical Mechanisms of Cholesterol Homeostasis
胆固醇稳态的生物物理机制
  • 批准号:
    10117604
  • 财政年份:
    2021
  • 资助金额:
    $ 29.1万
  • 项目类别:
Molecular Regulation of Fusion: Voltage Dependence and Local Physical Interaction
聚变的分子调控:电压依赖性和局部物理相互作用
  • 批准号:
    8824948
  • 财政年份:
    2013
  • 资助金额:
    $ 29.1万
  • 项目类别:
Molecular Regulation of Fusion: Voltage Dependence and Local Physical Interaction
聚变的分子调控:电压依赖性和局部物理相互作用
  • 批准号:
    8432279
  • 财政年份:
    2013
  • 资助金额:
    $ 29.1万
  • 项目类别:
Dynamics of Raft Formation and Growth
筏形成和生长的动力学
  • 批准号:
    7993055
  • 财政年份:
    2003
  • 资助金额:
    $ 29.1万
  • 项目类别:
Dynamics of Raft Formation and Growth
筏形成和生长的动力学
  • 批准号:
    8197570
  • 财政年份:
    2003
  • 资助金额:
    $ 29.1万
  • 项目类别:
Dynamics of Raft Formation and Growth
筏形成和生长的动力学
  • 批准号:
    6557539
  • 财政年份:
    2003
  • 资助金额:
    $ 29.1万
  • 项目类别:
Dynamics of Raft Formation and Growth
筏形成和生长的动力学
  • 批准号:
    7151231
  • 财政年份:
    2003
  • 资助金额:
    $ 29.1万
  • 项目类别:
Dynamics of Raft Formation and Growth
筏形成和生长的动力学
  • 批准号:
    6838820
  • 财政年份:
    2003
  • 资助金额:
    $ 29.1万
  • 项目类别:

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