Signal Integration in Neutrophil Chemotaxis

中性粒细胞趋化作用中的信号整合

• 批准号: 8840606
• 负责人: Orion D Weiner
• 金额: $ 34.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840606
• 关键词: Accounting; Actins; Action Potentials; Agonist; Animals; Atherosclerosis; Bacteria; Biological Process; Cell Polarity; Cells; Chemotaxis; Complex; Disease; Esthesia; Feedback; Genetic; Grant; Health; Immune; In Vitro; Individual; Inflammation; Life; Ligands; Logic; Mammalian Cell; Membrane; Molecular; Morphogenesis; Movement; Neoplasm Metastasis; Noise; Pathologic Processes; Play; Process; Receptor Signaling; Relative (related person); Role; Sensory; Signal Transduction; Source; Stimulus; System; Titrations; base; cell motility; combat; digital; in vivo; inhibitor/antagonist; killings; loss of function; migration; neutrophil; optogenetics; pathogen; reconstitution; research study; response; signal processing; tool

DESCRIPTION (provided by applicant): Neutrophils are innate immune cells that use directed migration to hunt and kill bacteria. This directed migration depends on several fundamental signaling capabilities. Neutrophils can migrate up chemotactic gradients spanning several orders of magnitude, requiring signaling adaptation so that cells respond to relative changes rather than steady-state concentrations of ligand. Neutrophils generate a consistent internal polarity that does not depend on the steepness of the external gradient, requiring positive feedback to amplify subtle signaling asymmetries and long-range inhibition so that protrusions can compete with one another to generate a dominant leading edge. Through genetic and pharmacological loss-of-function experiments, we know many of the core components required for chemotaxis. However, there are still fundamental gaps in our understanding of the how these signaling components interact to generate cell polarity and movement. Because the overall process of polarity is highly complex, we have developed tools to isolate and dissect individual steps in the signaling cascade to better understand the overall signaling circuit. In the last gran period, we developed a general approach for quantitative optogenetic control of intracellular signaling in mammalian cells. This system gives us unprecedented spatial and temporal control of a wide range of intracellular signals and will enable us to dissect the logic of signal processing in a manner that has not been possible with conventional tools. Quantitative control of intracellular signals has played a fundamental role in uncovering the logic of action potentials and bacterial chemotaxis, and we envision that our optogenetic tools will be similarly transformative for understanding cell polarity in neutrophils. Our specific aims are to understand the sensory adaptation that accounts for the remarkable dynamic range of chemotaxis (Aim 1) and to dissect the positive feedback loops (Aim 2) and long-range inhibition (Aim 3) that make neutrophil polarity possible.

描述（由申请人提供）：中性粒细胞是使用定向迁移狩猎和杀死细菌的先天免疫细胞。该定向迁移取决于几种基本信号传导功能。中性粒细胞可以迁移跨越几个数量级的趋化梯度，需要信号适应，从而使细胞响应相对变化而不是配体的稳态浓度。中性粒细胞会产生一致的内部极性，不取决于外部梯度的陡度，需要积极的反馈来扩大微妙的信号传导不对称和远距离抑制，从而使突起可以彼此竞争以产生主要的领先优势。通过遗传和药理功能丧失实验，我们知道趋化性所需的许多核心成分。但是，我们对这些信号成分如何相互作用以产生细胞极性和运动的理解中仍然存在根本的差距。由于极性的整体过程非常复杂，因此我们开发了隔离和剖析信号级联中各个步骤的工具，以更好地了解整体信号传导电路。在最后一个格兰时期，我们开发了一种通用方法，用于对哺乳动物细胞中细胞内信号传导的定量光遗传控制。该系统为我们提供了多种细胞内信号的前所未有的空间和时间控制，并将使我们能够以常规工具不可能的方式剖析信号处理的逻辑。细胞内信号的定量控制在发现动作电位的逻辑方面发挥了基本作用 和细菌趋化性，我们设想我们的光遗传学工具将类似地转化，以了解中性粒细胞中的细胞极性。我们的具体目的是了解趋化性的显着动态范围（AIM 1）的感觉适应性（AIM 1），并剖析正面反馈回路（AIM 2）和远距离抑制（AIM 3），使中性粒细胞极现可能。