Regulation of Leukocyte-Endothelial Interactions

白细胞-内皮相互作用的调节

• 批准号: 418496-2012
• 负责人: Robinson, Lisa
• 金额: $ 2.48万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=573686
• 关键词: Regulation; Leukocyte; Endothelial; Interactions

In vertebrate animals, white blood cells play an important role in the immune system by providing protection against bacterial, fungal, and viral infections. White blood cells patrol throughout the body looking for signs of infection. This immune cell surveillance involves interactions between white blood cells and the cells lining blood vessels. White cells are recruited to areas of injury by different signals, especially molecules called chemokines. Among the family of chemokines, one member, fractalkine, is found on the surface of cells lining blood vessels, and both attracts white cells and physically attaches them to blood vessels. When fractalkine on the surface of blood vessels sticks to its binding partner, CX3CR1, present on the surface of white blood cells, this sets in motion a cascade of molecular events within white cells that cause them to become "sticky", to cross the vessel lining and to enter into the underlying tissue. However, nothing is known about how fractalkine binding to CX3CR1 affects the blood vessels themselves. Our work suggests that contact between white cells and blood vessel fractalkine not only affects the white cells, but drastically alters the shape and function of blood vessel cells themselves. We observed that such contact causes gaps to form between cells of the vessel lining, allowing further tissue infiltration of white cells. This is the first demonstration that fractalkine is not merely a passive bystander that anchors white cells, but rather, plays a fundamental role in maintaining the blood vessel barrier. The proposed research will use state-of-the-art microscopy, cell biology, and biochemical techniques to examine how engaging fractalkine on the surface of blood vessels alters the structure, function, and barrier integrity of blood vessels. By understanding the molecular details, our studies will shed light on a fundamental process of immune cell patrolling conserved among vertebrate animals.

在脊椎动物中，白色血细胞通过提供针对细菌、真菌和病毒感染的保护而在免疫系统中发挥重要作用。 白色血细胞在全身巡逻，寻找感染的迹象。 这种免疫细胞监视涉及白色血细胞和血管内衬细胞之间的相互作用。 白色细胞通过不同的信号，特别是称为趋化因子的分子，被招募到损伤区域。 在趋化因子家族中，有一个成员，fractalkine，存在于血管内衬细胞的表面，两者都能吸引白色细胞并将它们附着在血管上。 当血管表面上的fractalkine粘附到其结合配偶体CX3CR 1上时，CX3CR 1存在于白色血细胞表面上，这在白色细胞内启动了一系列分子事件，导致它们变得“粘性”，穿过血管衬里并进入下层组织。然而，目前还不清楚fractalkine与CX3CR1的结合如何影响血管本身。 我们的工作表明，白色细胞和血管fractalkine之间的接触不仅影响了白色细胞，而且极大地改变了血管细胞本身的形状和功能。 我们观察到，这种接触导致血管衬里细胞之间形成间隙，允许白色细胞进一步组织浸润。 这是第一次证明fractalkine不仅仅是锚定白色细胞的被动旁观者，而是在维持血管屏障中起着重要作用。 拟议的研究将使用最先进的显微镜，细胞生物学和生物化学技术来研究血管表面的fractalkine如何改变血管的结构，功能和屏障完整性。通过了解分子细节，我们的研究将揭示脊椎动物中保守的免疫细胞巡逻的基本过程。