Understanding G-Protein Coupled Receptors
Understanding G-Protein Coupled Receptors
批准号:
6318929
负责人:
JENNIFER Jean LINDERMAN
金额:
$16.59万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-04-01 至 2004-03-31
关键词:
G protein G protein coupled receptor kinase biological signal transduction chemical association chemical kinetics chemical models computer simulation conformation dimer drug screening /evaluation high throughput technology inhibitor /antagonist intermolecular interaction ligands mathematical model model design /development molecular biology information system receptor receptor binding receptor coupling receptor expression statistics /biometry thermodynamics
中文摘要
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。
英文摘要
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.
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依托单位:
海外基金