On the emergence of polarization and motility responses from chemotactic networks

描述(由申请人提供)：许多真核细胞类型可以对化学诱导剂的外部梯度做出反应而极化。建立一个指向准确方向的内部指南针的能力对于酵母细胞交配、轴突在发育中的神经系统中找到自己的道路以及先天性免疫系统中的细胞发现和杀死入侵的病原体是至关重要的。细胞迁移调控不当与人类疾病密切相关，如动脉粥样硬化和癌症转移。了解生物网络如何动态控制趋化反应是在病理条件下开发有针对性干预的关键一步。中性粒细胞趋化网络中的许多成分和相互作用已经被确定。然而，目前还不知道趋化性的基本性质是如何从这些网络的详细分子描述中出现的。我们的长期目标是了解：1)信号网络是如何产生动态极化反应的；2)哪些极性特性对于指导有效的运动是必不可少的；3)在不同的运动细胞中使用什么一般机制来调节精确和有效的运动。在这里，我们打算研究人类中性粒细胞中的信号网络如何产生动态极化和运动反应。我们的具体目标是：1.识别控制极化动力学的趋化网络中的相互作用；2.对极化过程进行建模；以及3.识别引导有效运动所需的关键的极性表型。与公共卫生相关：真核细胞对外界化学信号作出反应而极化和迁移的能力对各种生物过程至关重要。虽然已经确定了趋化网络中的许多生化成分、相互作用和反馈，但一个主要的挑战仍然是理解如何从这些分子细节中产生刻板的极化和运动性反应。在这里，我们建议确定人类中性粒细胞信号网络中的来源，这些来源控制着趋化的关键反应特性。

DESCRIPTION (provided by applicant): Many eukaryotic cell types can polarize in response to an external gradient of chemoattractant. The ability to establish an internal compass that points in a precise direction is essential for yeast cells to mate, axons to find their way in the developing nervous system, and cells in the innate immune system to find and kill invading pathogens. Misregulation of cell migration is intimately involved in human disease, such as atherosclerosis and cancer metastasis. Understanding how biological networks dynamically control chemotactic responses is a key step towards developing targeted interventions in pathological conditions. Many of the components and interactions within neutrophil chemotaxis networks have been identified. However, it is not known how basic properties of chemotaxis emerge from detailed molecular descriptions of these networks. Our long term goals are to understand: 1) how dynamic polarization responses are generated by signaling networks; 2) which properties of polarity are essential for guiding efficient motility; 3) what general mechanisms are employed in diverse motile cells to regulate precise and efficient motility. Here, we propose to study how dynamic polarization and motility responses are generated by signaling networks in human neutrophils. Our specific aims are to: 1. Identify interactions within the chemotaxis network that control polarization dynamics; 2. Model the polarization process; and 3. Identify key polarity phenotypes that are required for guiding efficient motility. PUBLIC HEALTH RELEVANCE: The ability of eukaryotic cells to polarize and migrate in response to external chemical cues is essential for diverse biological processes. While many biochemical components, interactions, and feedbacks within chemotaxis networks have been identified, a major challenge remains to understand how stereotyped polarization and motility responses emerge from these molecular details. Here, we propose to identify sources within human neutrophil signaling networks that control key response properties of chemotaxis.