Modeling of chemotactic sensing in Dictyostelium

描述(由申请人提供)： 感知外部化学源的方向并通过极化和迁移向趋化剂或远离趋化剂(趋化性)做出反应的能力，对于单细胞生物体(如细菌和阿米巴)以及多细胞系统的正常运作至关重要。在发育过程中，几乎每种类型的细胞都会发生一定程度的趋化作用。虽然趋化性在先天免疫中的作用已经被认识了一个多世纪，但最近的证据表明，这种基本的细胞反应在发育和组织维持的许多方面发挥着重要作用。正常的生理过程，如淋巴细胞归巢、血管生成、胚胎生成、神经生成和伤口愈合，都需要特定细胞的准确迁移。不适当的趋化调节在过度炎症和炎症相关疾病中发挥作用，如哮喘、多发性硬化症和关节炎。 为了阐明控制这种双重调控的机制，我们需要了解刺激增量触发的时间反应与细胞在梯度中的空间反应是如何相关的。我们打算将数学分析与对这些酶的时间和空间变化的定量测量相结合，以解释经乳酸菌素处理和极化的细胞中的脂质水平。为此，我们计划开发一系列数学和计算模型，并在实验中进行验证。具体地说，我们建议1)确定3‘-磷酸肌醇酶的互补调节在外部梯度放大中的作用；2)开发一个基于Web的交互式Java小程序来演示梯度传感；3)表征几种正反馈机制对扩增的影响。

DESCRIPTION (provided by applicant): The ability to sense the direction of external chemical sources and respond by polarizing and migrating toward chemoattractants or away from chemorepellants - chemotaxis - is crucial for proper functioning of single cell organisms, such as bacteria and amoebae, as well as multi-cellular systems. Chemotaxis occurs to some extent in almost every cell type at some time during its development. While the role of chemotaxis in innate immunity has been appreciated for over a century, recent evidence suggests that this fundamental cellular response plays a major role in many aspects of development and tissue maintenance. Normal physiological processes such as lymphocyte homing, angiogenesis, embryogenesis, neurogenesis, and wound healing require accurate migration of specific cells. Inappropriate regulation of chemotaxis plays a role in excessive inflammation and inflammation-related diseases such as asthma, multiple sclerosis, and arthritis. To elucidate the mechanisms which control this dual regulation we need to appreciate how temporal responses triggered by stimulus increments relate to the spatial responses of cells in gradients. We intend to integrate mathematical analysis with quantitative measurements of the temporal and spatial changes in these enzymes to account for lipid levels in latrunculin-treated and polarized cells. To this end we plan to develop a series of mathematical and computational models and to validate them experimentally. Specifically, we propose 1) To determine the role of the complementary regulation of the 3' phosphoinositide enzymes in amplification of the external gradient; 2) To develop an interactive web-based Java applet to illustrate gradient sensing; 3) To characterize the effects on amplification of several positive feedback mechanisms.