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Deconstructing and constructing innate immune functions using molecular sensors and actuators

机译:使用分子传感器和执行器解构和构建先天免疫功能

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摘要

White blood cells such as neutrophils and macrophages are made competent for chemotaxis and phagocytosis - the dynamic cellular behaviors that are hallmarks of their innate immune functions - by the reorganization of complex biological circuits during differentiation. Conventional loss-of-function approaches have revealed that more than 100 genes participate in these cellular functions, and we have begun to understand the intricate signaling circuits that are built up from these gene products. We now appreciate: (1) that these circuits come in a variety of flavors - so that we can make a distinction between genetic circuits, metabolic circuits and signaling circuits; and (2) that they are usually so complex that the assumption of multiple feedback loops, as well as that of crosstalk between seemingly independent pathways, is now routine. It has not escaped our notice, however, that just as physicists and electrical engineers have long been able to disentangle complex electric circuits simply by repetitive cycles of probing and measuring electric currents using a voltmeter, we might similarly be able to dissect these intricate biological circuits by incorporating equivalent approaches in the fields of cell biology and bioengineering. Existing techniques in biology for probing individual circuit components are unfortunately lacking, so that the overarching goal of drawing an exact circuit diagram for the whole cell - complete with kinetic parameters for connections between individual circuit components - is not yet in near sight. My laboratory and others have thus begun the development of a new series of molecular tools that can measurably investigate the circuit connectivity inside living cells, as if we were doing so on a silicon board. In these proceedings, I will introduce some of these techniques, provide examples of their implementation, and offer a perspective on directions moving forward.
机译:通过分化过程中复杂的生物回路的重组,使白细胞(如嗜中性粒细胞和巨噬细胞)具有趋化性和吞噬能力,​​这些动态细胞行为是其固有免疫功能的标志。传统的功能丧失方法已经揭示了100多个基因参与了这些细胞功能,并且我们已经开始了解由这些基因产物构建的复杂信号转导电路。我们现在赞赏:(1)这些回路具有多种风味-因此我们可以区分遗传回路,代谢回路和信号回路; (2)它们通常是如此复杂,以至于现在假设多个反馈回路以及看似独立的通路之间的串扰都是假定的。但是,正如物理学家和电气工程师早就能够通过使用电压表进行重复的探测和测量电流的循环来解开复杂的电路一样,我们同样可以解剖这些复杂的生物电路通过在细胞生物学和生物工程领域整合等效方法。不幸的是,生物学中缺乏用于探测单个电路组件的现有技术,因此,在不久的将来还没有看到为整个细胞绘制精确的电路图(包括用于单个电路组件之间的连接的动力学参数)的总体目标。因此,我的实验室和其他实验室已经开始开发一系列新的分子工具,这些工具可以可测量地研究活细胞内部的电路连通性,就像我们在硅板上那样。在这些程序中,我将介绍其中一些技术,提供其实现示例,并就前进的方向提供一个观点。

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  • 会议地点 Baltimore MD(US)
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    Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205,Center for Cell Dynamics, Institute for Basic Biomedical Sciences, Johns Hopkins University, Baltimore, MD, 21205;

    Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205,Center for Cell Dynamics, Institute for Basic Biomedical Sciences, Johns Hopkins University, Baltimore, MD, 21205,Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205,Percursory Research for Embryonic Science and Technology Investigator, Japan Science and Technology Agency, Saitama 332-0012, Japan;

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