Unravelling the role of cellular microvesicles on lymphatic vessel function

揭示细胞微泡对淋巴管功能的作用

• 批准号: RGPIN-2016-05331
• 负责人: Martel, Catherine
• 金额: $ 1.82万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760593
• 关键词: Unravelling; role; cellular; microvesicles; lymphatic

Atherosclerosis is one of the leading causes of mortality and morbidity in Canada. It is driven by the accumulation of cholesterol and inflammatory cells in the blood vessel (artery) wall that build up what is called a "plaque". Much effort has been directed at increasing circulating levels of high density lipoprotein cholesterol (HDL-C, or "good cholesterol") to decrease plaque size and consequently, prevalence of coronary artery disease (CAD). However, raising plasma levels of HDL-C has met with disappointing clinical outcomes, suggesting that this strategy may not lead to an increased cholesterol mobilization capacity or prevent CAD. As there is an urge to better understand the cholesterol clearance process, beyond the transition of cholesterol onto cholesterol acceptors such as HDL, collaborators and I have focused on the path cholesterol acceptors are actually taking to leave plaque, and discovered a new prerequisite player in the modulation of cholesterol removal from the artery wall: the lymphatic system. As the lymphatic system - lymph, from Latin lympha, meaning water - generally governs the transport of macromolecules from the tissues to the blood and, accordingly, peripheral lymph contains cholesterol acceptors, a role in cholesterol transport seemed logical.Based on a strong scientific background acquired in Quebec and in the US, with world-renowned experts in cardiology and immunology, my team and I now aim to unravel the mechanisms leading to this abnormal lymphatic function observed in atherosclerosis onset and progression. Our recent work suggests that this impairment is most likely precociously associated with a defect in the pumping capacity of the lymphatic vessels to propel lymph down the road. Therefore, our goal is to identify the origin of this problem by pointing out whether and how lymph composition could affect the mechanical function of the lymphatic contractile units. As plaque also accumulates certain types of proatherogenic cell fragments called "microvesicles", we will more specifically test whether these waste products are contained in lymph and how they potentially modulate the lymphatic contraction capacity. In keeping with the mission of the NSERC, we will explore the lymphatic physiology beyond the edges, with the ultimate goal of discovering new modulators of lymphatic vessel function.

动脉粥样硬化是加拿大死亡率和发病率的主要原因之一。它是由胆固醇和炎症细胞在血管（动脉）壁中的积累驱动的，这些细胞形成了所谓的“斑块”。许多努力已经针对增加高密度脂蛋白胆固醇（HDL-C，或“好胆固醇”）的循环水平以减小斑块大小，并因此减小冠状动脉疾病（CAD）的患病率。然而，提高血浆HDL-C水平的临床结果令人失望，表明这种策略可能不会导致胆固醇动员能力增加或预防CAD。由于有一种更好地了解胆固醇清除过程的冲动，除了胆固醇向胆固醇受体（如HDL）的过渡之外，我和我的合作者专注于胆固醇受体实际上离开斑块的路径，并发现了一个新的先决条件参与者调节胆固醇从动脉壁中去除：淋巴系统。由于淋巴系统（lymph，拉丁语lympha，意思是水）通常控制大分子从组织到血液的运输，因此，外周淋巴含有胆固醇受体，胆固醇运输中的作用似乎是合理的。基于在魁北克和美国获得的强大科学背景，与世界知名的心脏病学和免疫学专家，我和我的团队现在的目标是解开导致动脉粥样硬化发病和进展中观察到的这种异常淋巴功能的机制。我们最近的研究表明，这种损伤很可能与淋巴管泵送淋巴液的能力缺陷有关。因此，我们的目标是通过指出淋巴成分是否以及如何影响淋巴收缩单位的机械功能来确定这个问题的起源。由于斑块还会积聚某些类型的促动脉粥样硬化细胞碎片（称为“微泡”），我们将更具体地测试淋巴中是否含有这些废物以及它们如何潜在地调节淋巴收缩能力。为了与NSERC的使命保持一致，我们将探索淋巴生理学的边缘之外，与发现淋巴管功能的新调节剂的最终目标。