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在化学引诱剂的外部梯度下发生极化。对于酵母细胞的交配，轴突在发育中的神经系统中找到自己的路，以及先天免疫系统中的细胞发现并杀死入侵的病原体来说，建立一个指向精确方向的内部指南针的能力是必不可少的。细胞迁移的错误调控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被确定。然而，尚不清楚趋化性的基本性质是如何从这些网络的详细分子描述中产生的。我们的长期目标是了解：1)信号网络如何产生动态极化响应；2)极性的哪些特性对于引导高效运动是必不可少的；3)不同运动细胞调节精确和有效运动的一般机制是什么？在这里，我们建议研究人类中性粒细胞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内的相互作用；2. 模拟极化过程；和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而极化和迁移的能力对多种生物过程至关重要。虽然趋化网络中的许多生化成分、相互作用和反馈已经被确定，但一个主要的挑战仍然是了解刻板极化和运动反应是如何从这些分子细节中产生的。在这里，我们建议在人类中性粒细胞信号网络中确定控制趋化性关键反应特性的来源。

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.