The Role of CD99 in Leukocyte Transendothelial Migration in vitro and in vivo

CD99 在体内外白细胞跨内皮迁移中的作用

• 批准号: 8525678
• 负责人: Richard L. Watson
• 金额: $ 4.72万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525678
• 关键词: Adhesives; Affect; Area; Arthritis; Atherosclerosis; Autoimmune Diseases; Autoimmunity; Automobile Driving; Behavior; Binding; Blood Vessels; Cell membrane; Cells; Characteristics; Chronic; Complex; Conflict (Psychology); Data; Disease; Endothelial Cells; Endothelium; Event; Extravasation; Four-dimensional; Goals; Healed; Image; Immigration; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intercellular Junctions; Lateral; Leukocytes; Life; Malignant Neoplasms; Membrane; Microscopy; Microtubules; Molecular; Movement; Pathologic; Physiological; Plasma; Play; Process; Proteins; Recruitment Activity; Recycling; Regulation; Reperfusion Injury; Reporting; Resolution; Reticulum; Role; Route; Series; Site; Stimulus; Structure; Surface; System; Techniques; Technology; Time; Tissues; Vesicle; Wound Healing; base; cell motility; chemokine; combat; cytokine; design; healing; human disease; in vivo; insight; interstitial; leukocyte mediator; microorganism; migration; new therapeutic target; novel; postcapillary venule; prevent; public health relevance; research study; response; trafficking

DESCRIPTION (provided by applicant): Inflammation is the body's most fundamental and critical response to infection or injury. In response to inflammatory stimuli, the local endotheliu is activated by cytokines and chemokines to recruit circulating leukocytes to the areas of tissue damage. This involves a complex, stepwise sequence of adhesive molecular interactions that occur between leukocytes and the endothelial cells comprising the vasculature. Arguably the most important step of inflammation is the movement of leukocytes through the endothelial barrier itself, in a process known as transendothelial migration (TEM). PECAM and CD99 are two proteins that have proven to be critical for leukocyte TEM. While PECAM's function in this process has been studied in depth, very little is known about CD99 and the mechanisms behind its actions. In addition to being expressed on leukocytes and along endothelial borders, PECAM and CD99 also partially reside in an interconnected reticular network of membrane vesicles just underneath the endothelial plasma membrane, known as the lateral border recycling compartment (LBRC). During TEM, membrane from the LBRC (containing PECAM and CD99) is trafficked to sites of transmigrating leukocytes in a process known as targeted recycling (TR). TR is thought to supply the migrating leukocyte with unligated PECAM and CD99 to engage the cell and facilitate its movement out of the vasculature. Blocking PECAM function inhibits TR from being initiated and subsequently prevents TEM. However, it is not known if CD99 plays a role in this complex process. By defining how CD99 operates on a molecular level, we will gain great insight into not only how TEM is regulated but also how to possibly control this step of inflammation. While it has been shown that CD99 functions downstream of PECAM during TEM in vitro, the reports thus far regarding its level of function and significance in TEM in vivo have been largely conflicting. However, the conclusions from these studies have all been based on the interpretations of static ex vivo images and not by viewing the events in real time or in living tissue. In order to fully understand the function of CD99, it is critical to study exactly how it functions spatio-temporally to regulate leukocyte TEM. With our state-of-the-art 4- dimensional imaging system, we possess a unique and powerful system for studying the events TEM in real time in vivo at unprecedented resolution. By utilizing this technology, we will gain a more thorough understanding of this important molecule and gain novel insight into not only the physiologic mechanism of inflammation, but be able to identify a number of novel therapeutic targets for various pathologic conditions such as atherosclerosis, autoimmune diseases, and cancer.

描述（由申请人提供）：炎症是人体对感染或损伤最基本、最关键的反应。为了响应炎症刺激，局部内皮细胞被细胞因子和趋化因子激活，将循环白细胞募集到组织损伤区域。这涉及白细胞和构成脉管系统的内皮细胞之间发生的复杂的、逐步的粘附分子相互作用序列。可以说，炎症最重要的步骤是白细胞穿过内皮屏障本身的运动，这一过程称为跨内皮迁移（TEM）。 PECAM 和 CD99 是两种已被证明对白细胞 TEM 至关重要的蛋白质。虽然 PECAM 在此过程中的功能已被深入研究，但对 CD99 及其作用背后的机制知之甚少。 除了在白细胞上和沿着内皮边界表达外，PECAM 和 CD99 还部分存在于内皮质膜下方的相互连接的膜囊泡网状网络中，称为侧缘回收区室 (LBRC)。在 TEM 过程中，来自 LBRC 的膜（包含 PECAM 和 CD99）被运输到白细胞迁移位点，这一过程称为靶向回收 (TR)。 TR被认为向迁移的白细胞提供未连接的PECAM和CD99以接合细胞并促进其移出脉管系统。阻断 PECAM 功能会抑制 TR 的启动，从而阻止 TEM。然而，尚不清楚 CD99 是否在这个复杂的过程中发挥作用。通过定义 CD99 在分子水平上的运作方式，我们不仅可以深入了解 TEM 的调节方式，还可以深入了解如何控制炎症的这一步骤。 虽然已经表明 CD99 在体外 TEM 过程中在 PECAM 下游发挥作用，但迄今为止关于其在体内 TEM 中的功能水平和重要性的报道在很大程度上是相互矛盾的。然而，这些研究的结论都是基于静态离体图像的解释，而不是通过实时或活体组织中的事件观察。为了充分了解CD99的功能，准确研究它如何在时空上调节白细胞TEM至关重要。 凭借我们最先进的 4 维成像系统，我们拥有独特而强大的系统，可以以前所未有的分辨率实时研究活体 TEM 事件。通过利用这项技术，我们将更深入地了解这一重要分子，不仅对炎症的生理机制有新的见解，而且能够针对动脉粥样硬化、自身免疫性疾病等各种病理状况确定许多新的治疗靶点和癌症。