LOCAL THERMOGENESIS IN LYMPHATIC VESSEL/NODE FUNCTION

淋巴管/淋巴结功能中的局部生热作用

基本信息

批准号：
8846004
负责人：
Gwendalyn J Randolph
金额：
$ 22.19万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8846004
关键词：
Address Adipocytes Adipose tissue Adult Affect Aging Anatomy Antiatherogenic Antigens Aorta Apolipoprotein E Arterial Fatty Streak Arteries Body Temperature Brown Fat CX3CL1 gene Cardiovascular Diseases Cells Cholesterol Defect Dendritic Cells Depressed mood Development Ear Energy Metabolism Exhibits Failure Fatty acid glycerol esters Fever Fluid Balance Health Heart Heating High Density Lipoprotein Cholesterol Human Immune Immune response Immune system Immunity Incidence Infection Liquid substance Location Lung Lymph Lymphatic Lymphatic Capillaries Lymphatic System Lymphatic vessel Mediating Monitor Mouse Strains Movement Mus Muscle Cells Mutant Strains Mice Nutrient Organ Organism Play Predisposition Process Property Rodent Role Running Series Skin Stress Structure System T-Lymphocyte Techniques Temperature Testing Thermogenesis Tissues Tracer Tunica Adventitia Vascular Endothelial Growth Factor Receptor-3 Waste Products adaptive immunity blind cardiovascular health chemokine receptor fighting hypercholesterolemia improved interest lymph nodes mitochondrial uncoupling protein mouse model nutrient absorption pathogen research study response subcutaneous trafficking uncoupling protein 1 whole body imaging

项目摘要

DESCRIPTION (provided by applicant): The lymphatic system, including lymphatic vessels and lymph nodes (LNs), crucially regulates fluid balance, nutrient absorption, and immunity. Blind-ended lymphatic capillaries take up fluid and immune cells in all organs. These vessels coalesce into so-called lymphatic collecting vessels that drain to and from LNs. Collecting vessels, surrounded by specialized muscle cells, control the rate and magnitude of lymph transport throughout the lymphatic system. Both collecting vessels and LNs are inevitably surrounded by adipose tissue. Interestingly, the adipose tissue surrounding prominent LNs and lymphatic collecting vessels in rodents is "beige" fat -subcutaneous fat depots that can undergo adaptive thermogenesis, a transition from a character consisting predominantly of white, energy-storing unilocular adipocytes to those of brown multilocular adipocytes that express UCP-1. Brown adipocytes generate heat using the mitochondrial uncoupling protein 1 (UCP-1), and UCP-1 is essential for its thermo genic properties. Importantly, beige adipose tissue has been discovered in adult humans and whole body images show depots of brown fat in adults that colocalize with classic locations of LNs, resembling beige subcutaneous depots of the mouse, which inevitably encase LNs. Indeed, recent histological analysis confirms that adipose depots containing brown adipocytes colocalize with LNs in humans, as they do in mice. Beige fat is also found around the human heart and major arteries, as observed in mice as well. While the function of brown fat in generating heat under conditions of cold stress is well appreciated, only a few studies have addressed whether the anatomical locations of brown or beige fat are important. That is, does the location of heat-generating fat provide essential local thermogenesis to maintain particular functions? Perhaps the primary role of brown fat as a thermogenic organ is key and that increasing local temperature through UCP-1 induction would improve lymphatic transport, since lymphatic transport in intact vessels is known to increase substantially with fever-range elevations in temperature. Thus, we hypothesize that thermogenesis in beige fat plays a key role in supporting the lymphatic system, including transport of cargo through the lymphatic vasculature (such as HDL-cholesterol, or antigens) and overall functionality of the adjacent lymph node. In aim 1, we will investigate whether thermogenesis around lymph nodes and surrounding lymphatic vessels supports lymphatic transport to lymph nodes and maintains immune responses, particularly in the context of cold challenge. In aim 2, we will investigate the functional consequences that loss of UCP-1-generated heat has on local lymphatic transport, including an analysis of implications for cardiovascular disease considering that lymphatic vessels mediate the movement of cholesterol out of the aortic wall.

描述（由申请人提供）：淋巴系统，包括淋巴管和淋巴结（LN），对体液平衡、营养吸收和免疫力起着至关重要的调节作用。盲端毛细淋巴管吸收所有器官中的液体和免疫细胞。这些血管合并成所谓的淋巴收集管，流入或流出淋巴结。被专门的肌肉细胞包围的收集血管控制着整个淋巴系统的淋巴运输的速度和强度。集合管和淋巴结都不可避免地被脂肪组织包围。有趣的是，啮齿动物中突出的淋巴结和淋巴集合管周围的脂肪组织是“米色”脂肪皮下脂肪库，可以进行适应性产热，这是从主要由白色、能量储存的单房脂肪细胞组成的特征转变为棕色多房脂肪细胞的特征表达 UCP-1。棕色脂肪细胞利用线粒体解偶联蛋白 1 (UCP-1) 产生热量，而 UCP-1 对于其生热特性至关重要。重要的是，在成年人中发现了米色脂肪组织，全身图像显示成年人体内的棕色脂肪库与淋巴结的经典位置共存，类似于小鼠的米色皮下脂肪库，不可避免地包裹着淋巴结。事实上，最近的组织学分析证实，在人类体内，含有棕色脂肪细胞的脂肪库与 LN 共存，就像在小鼠体内一样。正如在小鼠身上观察到的那样，米色脂肪也存在于人类心脏和主要动脉周围。虽然棕色脂肪在冷应激条件下产生热量的功能已得到充分认识，但只有少数研究探讨了棕色脂肪或米色脂肪的解剖位置是否重要。也就是说，产热脂肪的位置是否提供必要的局部生热作用以维持特定功能？也许棕色脂肪作为产热器官的主要作用是关键，并且通过 UCP-1 诱导提高局部温度将改善淋巴运输，因为已知完整血管中的淋巴运输会随着发烧范围内的温度升高而大幅增加。因此，我们假设米色脂肪的生热作用在支持淋巴系统方面发挥着关键作用，包括通过淋巴脉管系统运输货物（例如高密度脂蛋白胆固醇或抗原）以及邻近淋巴结的整体功能。在目标 1 中，我们将研究淋巴结周围和周围淋巴管周围的生热作用是否支持淋巴液转运至淋巴结并维持免疫反应，特别是在寒冷挑战的情况下。在目标 2 中，我们将研究 UCP-1 产生的热量损失对局部淋巴运输的功能影响，包括分析考虑到淋巴管介导胆固醇从主动脉壁移出对心血管疾病的影响。