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Understanding G-Protein Coupled Receptors

了解 G 蛋白偶联受体

基本信息

批准号：
6636617
负责人：
JENNIFER Jean LINDERMAN
金额：
$ 16.54万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2005-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (Verbatim from the Applicant's Abstract): The overall, long term goal of this work is to develop ways to manipulate cellular responses initiated by ligand/receptor binding; this is done through the combination of mathematical modeling and experiment. The proposed work focuses on developing mathematical models for guanine nucleotide binding protein (G-protein) coupled receptors and G-protein activation. G-proteins are found in virtually every tissue, and they play key roles in, for example, the immune system, vision, brain function, and heart regulation. The activation of G-proteins by receptors at the cell surface initiates a signal transduction pathway that is complex and poorly understood. Receptors can exist in multiple states (active, inactive, ligand-bound, desensitized, internalized, etc.) and these states influence G-protein activation. Further, the kinetics of the transitions between receptor states appear to be important in determining levels and dynamics of G-protein activation and thus a variety of cellular responses. Despite the obvious complexity and dynamics of these signaling processes, most work in the field concentrates on relatively simple equilibrium models of the system. More accurate models of G-protein coupled receptors and G-protein activation are essential to understanding how effective bound ligands are at eliciting cellular responses. Such information is critical to the rational manipulation of cell function for purposes of cell and tissue engineering, and for the development of methods for the development and/or discovery of new phamaceuticals. In this proposal, kinetic models of the G-protein coupled receptor signaling pathway will be developed. Specifically, we will use these models to (1) test the hypothesis that ligand efficacy may be dramatically manipulated by altering cellular parameters, (2) demonstrate the influence that ligand-specific parameters have on signaling and desensitization, and (3) demonstrate conditions under which receptor dimerization may cause larger scale clustering and thus influence signaling. Finally, (4) we will test the hypothesis that common high throughput drug screening assays may be biased against the detection of a class of ligands known as inverse agonists. In each case, models will be used to make predictions that are experimentally accessible and have application to a wide range of G-protein coupled receptor systems.

描述(逐字摘自申请人的摘要)：总体的、长期的这项工作的目标是开发出操纵启动的细胞反应的方法通过配体/受体结合；这是通过结合数学建模和实验。拟议的工作重点是开发鸟嘌呤核苷酸结合蛋白(G蛋白)偶联的数学模型受体和G蛋白激活。G蛋白在几乎所有的组织，它们在免疫系统、视力、大脑功能和心脏调节。受体对G蛋白的激活作用在细胞表面启动了一条复杂的信号转导途径人们对此知之甚少。受体可以以多种状态存在(活动、非活动、配体结合、不敏感、内化等)而这些州影响着 G蛋白激活。此外，受体之间的转换的动力学状态似乎在决定G蛋白的水平和动态方面很重要激活，从而产生各种细胞反应。尽管很明显这些信令过程的复杂性和动态性，大多数都是在现场工作专注于系统的相对简单的均衡模型。更多 G蛋白偶联受体和G蛋白激活的准确模型是对于理解结合配体在诱导过程中的有效性是必不可少的细胞反应。这样的信息对理性操纵至关重要用于细胞和组织工程的细胞功能，以及开发和/或发现新的医药公司。在这一建议中，G蛋白偶联受体信号的动力学模型将开发路径。具体地说，我们将使用这些模型来(1)测试配基效能可以通过改变来戏剧性地操纵的假设细胞参数，(2)显示配基特异性的影响参数对信号和脱敏有影响，以及(3)论证受体二聚化可能导致更大规模聚集的条件从而影响信号传递。最后，(4)我们将检验假设常见的高通量药物筛选试验可能对检测一类称为反向激动剂的配体。在每种情况下，模型将用于进行可通过实验访问的预测，并具有广泛应用于G蛋白偶联受体系统。