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Cycle Representations of Receptor Complex Signal Transduction

受体复合物信号转导的循环表示

基本信息

批准号：
1951646
负责人：
Gregory Conradi Smith
金额：
$ 30万
依托单位：
College of William and Mary
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1951646&HistoricalAwards=false
关键词：
Cycle Representations Receptor Complex Signal

项目摘要

The border of living cells is covered with sentry molecules that sense the presence of chemical signals, assess the current situation, and initiate decision processes that determine a cell’s response to its environment. These “cell surface receptors” function like a car ignition switch: they accept a specific chemical signal (the key) and then communicate the presence of this chemical key to the interior of the cell. Because receptors have a profound influence on cell behavior, it is crucial to understand the details of how they function. The most important types of receptors are made up of several component parts that work together as complex molecular machines. Because of this complexity, mathematical models of cell surface receptors are integral to understanding both natural signaling mechanisms of cells and the mode of action of man-made therapeutic drugs. Mathematical and biophysical theory being developed by the PI is revealing how receptor function may be understood in terms of the properties of their parts (protein subunits) and the energetic interactions between these parts (conformational coupling). This fundamental scientific knowledge is the launching point for numerous applied endeavors that directly impact human wellbeing, such as scientifically informed drug development. In more technical terms, the PI’s recent mathematical work on cycle bases of product graphs provides a formalism for the efficient enumeration the possible modes of conformational coupling in a receptor dimer or high-order oligomer, beginning with arbitrary hypothesized monomeric state-transition diagram. This novel quantitative pharmacology modeling technique automatically satisfies the emergent thermodynamic constraints that arise in the receptor oligomer, and provides an unambiguous physical interpretation of each allosteric parameter. The PI is developing a general mathematical formalism, based on product graphs, for analysis of receptor complexes, with specific focus on dimeric G-protein-coupled receptors and receptor tyrosine kinases. The formalism will be extended to accommodate non-equilibrium phenomena mediated by nucleotide exchange. Software for the analysis of receptor oligomers will be developed and shared with life scientists. Because few mathematicians have the requisite biological background to be of help to medical scientists, and few medical scientists have the quantitative skills necessary to reverse engineer living cells, the PI is committed to training Ph.D. scientists who will have an interdisciplinary outlook, to exposing pre-medical undergraduates to the sophisticated mathematics, and to pedagogical writing that clarifies how mathematics is essential to progress in the life sciences. This award is co-funded with the Cellular Dynamics and Function program in Division of Molecular and Cellular Biosciences, and the Life Science Venture Fund in DMS.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

活细胞的边界覆盖着哨兵分子，它们感知化学信号的存在，评估当前情况，并启动决定细胞对其环境的反应的决策过程。这些“细胞表面受体”的功能就像汽车点火开关：它们接受特定的化学信号（钥匙），然后将该化学钥匙的存在传达给细胞内部。由于受体对细胞行为具有深远的影响，因此了解它们如何发挥作用的细节至关重要。最重要的受体类型由几个组成部分组成，这些组成部分作为复杂的分子机器一起工作。由于这种复杂性，细胞表面受体的数学模型对于理解细胞的自然信号传导机制和人造治疗药物的作用模式至关重要。 PI 正在开发的数学和生物物理理论揭示了如何根据受体的各个部分（蛋白质亚基）的特性以及这些部分之间的能量相互作用（构象耦合）来理解受体的功能。这一基础科学知识是许多直接影响人类福祉的应用努力的起点，例如科学药物开发。用更专业的术语来说，PI 最近关于产物图循环基础的数学工作为有效枚举受体二聚体或高阶寡聚体中构象耦合的可能模式提供了一种形式，从任意假设的单体状态转换图开始。这种新颖的定量药理学建模技术自动满足受体寡聚物中出现的新的热力学约束，并为每个变构参数提供明确的物理解释。 PI 正在开发一种基于产物图的通用数学形式，用于分析受体复合物，特别关注二聚体 G 蛋白偶联受体和受体酪氨酸激酶。该形式主义将扩展到适应由核苷酸交换介导的非平衡现象。将开发用于分析受体寡聚物的软件并与生命科学家共享。由于很少有数学家具备为医学科学家提供帮助所需的生物学背景，也很少有医学科学家具备对活细胞进行逆向工程所需的定量技能，因此 PI 致力于培养博士生。具有跨学科视野的科学家，让医学预科生接触复杂的数学，以及阐明数学对于生命科学进步的重要性的教学写作。该奖项由分子和细胞生物科学部的细胞动力学和功能项目以及 DMS 的生命科学风险基金共同资助。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。