Dynamics and mechanism of mechanical regulation of bacterial flagellar motor swit

描述(申请人提供)：鞭毛旋转是细菌移动的主要机制之一，对于生物膜的形成是必不可少的。许多细菌使用跨膜电化学梯度(H+或Na+)来驱动跨膜鞭毛马达的旋转。在BFM扭矩产生和CW-CCW切换方面，有大量但独立的实验和建模工作。然而，伯格实验室最近观察到，马达开关的动态受到负载和趋化信号的影响。电机开关频率先增加，然后随着外部负载的增加而减少。这一现象被认为具有功能作用。理解这些结果需要对扭矩产生和切换进行统一处理。在这项拟议的研究中，我们的目标是在现有实验数据的基础上建立描述鞭毛电机切换和扭矩产生的综合模型，具体目的有以下三个：1)建立与负载相关的切换动力学的数学模型和机制。我们将推广构象扩散模型，包括切换率对电机扭矩的依赖关系，这是直接从测量的扭矩-速度关系获得的，并评估各种机制。初步研究证实了该程序的有效性。2)研究与负载相关的开关动力学可能的功能作用。我们将使用在目标1和目标2中开发的模型来检验在Chey-P浓度波动下的多运动动力学。这项拟议的研究将通过与霍华德·伯格(哈佛大学)、Keiichi Namba(大阪大学)、Richard Berry(牛津大学)和David Blair(犹他大学)的实验室合作进行。相应的实验将在这些实验室中进行。我们将系统地检查现有的实验结果，桥梁和整合静态结构信息和动态数据，并使可检验的预测平行于其他几个实验室的实验研究。它将把对BFM功能的研究放在更广泛的细胞生理学调节的背景下。

DESCRIPTION (provided by applicant): Flagellar rotation is one of the major mechanisms for bacterial mobility, and is essential for biofilm formation. Many bacteria use the transmembrane electrochemical gradient (H+ or Na+) to power rotation of the transmembrane flagellar motor. There are extensive but separate experimental and modeling efforts on BFM torque generation and CW-CCW switching. However, recently the Berg lab observed that the motor switch dynamics is affected by the load as well as chemotactic signals. A motor switching frequency increases first but then decreases upon increasing the external load. This phenomenon is suggested to have functional roles. Understanding these results requires a unified treatment of torque generation and switching. In this proposed research, we aim at constructing an integrated model describing flagellar motor switching and torque generation based on available experimental data, with the following three specific aims: 1) Construct a mathematical model and examine mechanism for the load-dependent switching dynamics. We will generalize the conformational spread model by including the dependence of switching rates on motor torque, which is obtained directly from the measured torque-speed relations, and evaluate various mechanisms. Preliminary studies have confirmed validity of the procedure. 2) Examine possible functional roles of load-dependent switching dynamics. We will use the models developed in Aim 1 and 2 to examine multi-motor dynamics under fluctuating CheY-P concentrations. The proposed research will be performed through collaborating with the labs of Howard Berg (Harvard University), Keiichi Namba (Osaka University), Richard Berry (Oxford University), and David Blair (University of Utah). Corresponding experiments will be performed in these labs. We will systematically examine the existing experimental results, bridge and integrate static structural information and dynamic data, and make testable predictions parallel to the experimental studies in several other labs. It will place studies of BFM functions in the broader context of cell physiology regulations.