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向化学引诱物或远离化学排斥物（趋化性）迁移来响应的能力对于单细胞生物体（如细菌和变形虫）以及多细胞系统的正常功能至关重要。几乎每一种细胞类型在其发育过程中的某个时候都会在一定程度上发生趋化性。虽然趋化性在先天免疫中的作用已经认识了世纪，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起着重要作用。正常的生理过程如淋巴细胞归巢、血管生成、胚胎发生、神经发生和伤口愈合需要特定细胞的准确迁移。趋化性的不适当调节在过度炎症和炎症相关疾病如哮喘、多发性硬化和关节炎中起作用。 为了阐明控制这种双重调节的机制，我们需要了解刺激增量触发的时间响应如何与梯度中细胞的空间响应相关。我们打算将数学分析与这些酶的时间和空间变化的定量测量相结合，以解释latrunculin处理和极化细胞中的脂质水平。为此，我们计划开发一系列的数学和计算模型，并验证他们的实验。具体而言，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）开发基于Web的交互式Java applet来说明梯度传感; 3）表征几种正反馈机制对放大的影响。

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.