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响应于化学引诱物的外部梯度而增殖。建立指向精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方向以及先天免疫系统中的细胞找到并杀死入侵病原体至关重要。细胞迁移的失调与人类疾病如动脉粥样硬化和癌症转移密切相关。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的干预措施的关键一步。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，目前还不知道如何从这些网络的详细分子描述中出现趋化性的基本属性。我们的长期目标是了解：1）信号网络如何产生动态极化反应; 2）极性的哪些特性对于指导有效的运动至关重要; 3）在不同的运动细胞中采用哪些一般机制来调节精确和有效的运动。在这里，我们建议研究如何动态极化和运动反应产生的信号网络在人类中性粒细胞。我们的具体目标是：1.确定控制极化动力学的趋化性网络内的相互作用; 2.模拟极化过程;以及3.确定指导有效运动所需的关键极性表型。公共卫生相关性：真核细胞响应外部化学信号的迁移和迁移能力对于各种生物过程是必不可少的。虽然许多生化成分，相互作用，并在趋化性网络的反馈已被确定，一个主要的挑战仍然是了解如何定型极化和运动反应出现从这些分子的细节。在这里，我们建议确定人类中性粒细胞信号网络控制的趋化性的关键响应特性的来源。

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.