Survival Probability Approaches and Scalable Algorithms to Elucidate Molecular-Tether Reactions in Immunoreception and Cell Mechanics

阐明免疫接收和细胞力学中分子系链反应的生存概率方法和可扩展算法

• 批准号: 2052668
• 负责人: Jun Allard
• 金额: $ 27.34万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2052668&HistoricalAwards=false
• 关键词: Survival; Probability; Approaches; Scalable; Algorithms

Much of biological inquiry has focused on the chemically-active parts of proteins that have a stable, rigid shape. However, over 30% of our proteins have regions that are not rigid, but rather are floppy tethers that connect the chemically-active regions. Two examples of tethers are: immunoreceptors, the proteins involved in how immune cells receive signals from other cells; and formins, proteins that maintain the cell's architectural skeleton and are hijacked by invading bacteria including cholera. Tethers are easy to overlook. In part, this is because the mathematical descriptions that allow understanding of rigid proteins do not work for tethers. Therefore, mathematically characterizing tethers may lead to novel avenues of research in biology and medicine that were missed by focusing only of the rigid regions of proteins. This project will develop a mathematical description of tethers. The mathematics will be used to, first, develop a rapid computational algorithm to simulate the first few steps of how immune cells respond to external signals, including how they respond to off-switch signals through the protein PD-1, signals that is exploited by cancers to evade immune detection. Second, the mathematics will be used to study the tethers in formins. The resulting mathematics will create new connections between two separate fields of mathematics: stochastic process theory, and polymer physics. The project will also result in the training of graduate students with skills in immunology, cell biology, applied mathematics, computational science, and biophysics. Open-access resources for enabling computational science researchers will also be developed. These will have a special focus on creating tools for research in the remote era, including tutorials for high school and undergraduate students. Many proteins (around 30% in humans) have regions that lack well-defined structure, but rather fluctuate through an ensemble of configurations characterized by high intrinsic disorder. Many of these act as tethers that connect chemical reaction sites. Examples include immunoreceptors like the T Cell Receptor, PD1 and CD28, and formins, which regulate cytoskeleton assembly. Tethered reactions are ubiquitous; they have properties that are fundamentally distinct from standard solution reactions, requiring novel mathematical characterization; they are exploited by biology; and, in some cases, they provide novel avenues for therapeutics. This project exploits and extends a long-known mathematical correspondence between stochastic process theory and polymer physics to study tethered reactions. The mathematical theory aims to resolve biological mysteries, first, concerning the formin tethers and their ability to assemble the cytoskeleton even when bound at both termini, in a force-responsive manner. Second, the project addresses experimental data on immunoreceptor tethered signaling that cannot be explained by models that omit volume exclusion (crowding). The project will also develop 3 online resources that will help the Mathematical Biology community thrive in a future dominated by online interaction, including tutorials for high school and undergraduate students.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.

许多生物学研究都集中在蛋白质中具有稳定刚性形状的化学活性部分。然而，超过30%的蛋白质区域不是刚性的，而是连接化学活性区域的软栓。系绳的两个示例是：免疫受体，这种蛋白质参与免疫细胞如何接收来自其他细胞的信号;以及formin，这种蛋白质维持细胞的结构骨架，并被入侵的细菌（包括霍乱）劫持。系绳很容易被忽视。在某种程度上，这是因为允许理解刚性蛋白质的数学描述不适用于系链。因此，数学上表征系链可能会导致生物学和医学研究的新途径，而这些途径只关注蛋白质的刚性区域。这个项目将开发一个数学描述的系绳。首先，数学将用于开发一种快速计算算法，以模拟免疫细胞如何响应外部信号的前几个步骤，包括它们如何通过蛋白质PD-1响应关闭开关信号，这些信号被癌症用来逃避免疫检测。第二，数学将被用来研究福尔明的系绳。由此产生的数学将在两个独立的数学领域之间建立新的联系：随机过程理论和聚合物物理学。该项目还将培养具有免疫学、细胞生物学、应用数学、计算科学和生物物理学技能的研究生。还将开发开放获取的资源，使计算科学研究人员能够获得这些资源。这些课程将特别关注为远程时代的研究创建工具，包括高中和本科生的教程。许多蛋白质（人类中约30%）具有缺乏明确结构的区域，而是通过以高度内在无序为特征的整体构型波动。其中许多充当连接化学反应位点的系绳。例子包括免疫受体，如T细胞受体，PD 1和CD 28，以及调节细胞骨架组装的formin。栓系反应无处不在;它们具有与标准溶液反应根本不同的性质，需要新的数学表征;它们被生物学利用;并且在某些情况下，它们为治疗提供了新的途径。该项目利用并扩展了随机过程理论和聚合物物理学之间的长期数学对应关系，以研究栓系反应。数学理论旨在解决生物学上的谜团，首先是关于双链分子及其组装细胞骨架的能力，即使是在两端都被束缚的情况下，也是以力响应的方式。其次，该项目解决了免疫受体束缚信号的实验数据，这些数据无法通过忽略体积排除（拥挤）的模型来解释。该项目还将开发3个在线资源，帮助数学生物学社区在未来由在线互动主导的环境中蓬勃发展，包括高中和本科生的教程。该奖项反映了NSF的法定使命，并被认为值得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来支持。