Uncovering mechanisms of phagocytosis by class A scavenger receptors

揭示 A 类清道夫受体的吞噬机制

• 批准号: RGPIN-2015-05757
• 负责人: Bowdish, Dawn
• 金额: $ 3.28万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629493
• 关键词: Uncovering; mechanisms; phagocytosis; class; scavenger

Phagocytosis is an evolutionarily conserved process that likely originated to facilitate nutrient uptake in single-celled organisms and subsequently became essential to host-defence and homeostasis in multi-cellular organisms. The macrophage class A scavenger receptors are non-opsonic phagocytic receptors that recognize a number of natural (e.g. bacteria, modified lipoproteins) and synthetic ligands. Like other non-opsonic phagocytic receptors, they have no conventional signalling motifs in their cytoplasmic domains and yet transmit a phenomenal amount of information upon ligand recognition and uptake. We hypothesize that that the scavenger receptors contain previously uncharacterized motifs that contribute to phagocytosis and pro-inflammatory signalling, testable by these objectives;1) Discover functional domains in the scavenger receptors using ancient and modern genetics.2) Discover the role of lipid composition and transient lipid phases in scavenger receptor uptake. 3) Understand how cellular localization affects scavenger receptor signalling. Attempts to use traditional biochemical techniques to discover novel signalling motifs have provided insights into residues required for uptake, but have not been as fruitful as similar studies in opsonic receptors. We have shown (PMID:23181696) that a phylogenetic approach to discover evolutionarily conserved and divergent areas within these receptors provides a rich and robust method of attributing function to specific sequences and will expand and refine this approach in (Obj 1) by including studies of ancient (pre-mammalian) and modern (primates "> We have recently discovered that the scavenger receptors may depend more heavily on interactions with membrane lipids to initiate phagocytosis than the opsonic receptors (e.g. Fc receptors). We will elucidate these lipid interactions using high resolution microscopy to track scavenger receptor mobility in membranes (Obj 2). We have also determined that scavenger receptors collaborate with other innate immune receptors (i.e. the toll like receptors) but that their contribution to signalling is fundamentally different based on whether they are localized to the plasma membrane or the endosomal membrane. We have developed a number of molecular biology and cellular biology assays to dissect this interaction (Obj 3) and believe that this may be a heretofore undescribed mechanism of "fine-tuning" physiological responses to bacteria. The long-term goal of my research program is to understand the signalling processes of the non-opsonic phagocytic receptors. Since phagocytic receptors are essential for nutrient acquisition, host defence and multi-cellularity in lower organisms, and homeostasis and host defence in higher organisms, understanding the signalling capacity of these receptors will contribute to many biological questions.

吞噬作用是一种进化保守的过程，可能起源于单细胞生物中的营养吸收，随后对多细胞生物体的宿主防御和稳态至关重要。巨噬细胞A类清道夫受体是非上opsonic吞噬受体，它们识别许多天然（例如细菌，改良的脂蛋白）和合成配体。与其他非上吞噬受体一样，它们在其细胞质结构域中没有常规的信号传导基序，但在配体识别和摄取时会传递出惊人的信息。我们假设，清道夫受体包含以前没有特征的基序，这些基序有助于吞噬和促炎信号传导，可以通过这些目标来检验； 1）使用古代和现代遗传学发现在寻宝据受体中的功能域。2）清道夫受体吸收中的瞬时脂质相。 3）了解细胞定位如何影响清道夫受体信号传导。尝试使用传统的生化技术发现新型信号传导的尝试提供了对摄取所需的残基的见解，但并不像Opsonic受体中的类似研究那样富有成果。我们已经表明（PMID：23181696）表明，在这些受体中发现进化保守和不同的区域的系统发育方法为特定序列归因于特定序列提供了丰富而强大的方法，并将通过包括在（OBJ 1）中扩展和完善这种方法（OBJ 1）。古代（哺乳动物前）和现代（灵长类动物”>我们最近发现，与Opsonic受体相比，寻宝受体可能更依赖于与膜脂质的相互作用（例如FC受体）。分辨率显微镜在膜上跟踪清道夫受体迁移率（OBJ 2）。质膜或内体膜。我们开发了许多分子生物学和细胞生物学测定法（OBJ 3），并认为这可能是迄今为止的“微调”生理反应的未描述的机制。 我的研究计划的长期目标是了解非上吞噬受体的信号传导过程。由于吞噬受体对于养分获取至关重要，较低生物体中的宿主防御和多细胞性，以及较高生物体中的体内平衡和宿主防御，因此了解这些受体的信号传导能力将导致许多生物学问题。