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，包括淋巴血管和淋巴结（LNS），至关重要地调节液体平衡，营养吸收和免疫力。盲型淋巴毛细血管在所有器官中占用液体和免疫细胞。这些血管合并成所谓的淋巴收集血管，这些血管排水到LNS。收集的血管被专门的肌肉细胞包围，控制整个淋巴系统的淋巴传输的速率和幅度。两种收集的容器和LN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LN和淋巴收集血管周围的脂肪组织是“米色”脂肪的脂肪 - 皮肤脂肪仓库，它们可以经历适应性热，这是从由白色，能量存储的单方面脂肪组成的特征转变为棕色多脂质细胞，这些角色向棕色多圆膜脂肪细胞的角色，这些角色的脂肪细胞的脂肪细胞，这些特征的表现为表达ucc-1。棕色脂肪细胞使用线粒体解偶联蛋白1（UCP-1）产生热量，而UCP-1对于其热植物特性至关重要。重要的是，已经在成年人中发现了米色脂肪组织，整个身体图像显示了成年人与经典LNS共定位的棕色脂肪库，类似于小鼠的米色皮下仓库，这不可避免地要加密LN。实际上，最近的组织学分析证实，含有棕色脂肪细胞的脂肪仓库与人类中的LNS共定位，就像在小鼠中一样。在小鼠中也观察到的，在人心脏和主要动脉周围也发现了米色脂肪。虽然对棕色脂肪在冷应激条件下产生热量的功能受到很好的赞赏，但只有少数研究解决了棕色或米色脂肪的解剖位置是否重要。也就是说，产生热脂肪的位置是否提供了维持特定功能的必不可少的局部热发生？棕色脂肪作为热器官的主要作用可能是关键，并且通过UCP-1诱导升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大大增加，并且温度升高。因此，我们假设米色脂肪中的热发生在支持淋巴系统中起关键作用，包括通过淋巴管的运输（例如HDL-胆固醇或抗原）和邻近淋巴结的整体功能。在AIM 1中，我们将研究淋巴结和周围淋巴血管周围的热发生是否支持淋巴传输到淋巴结并保持免疫反应，尤其是在冷挑战的背景下。在AIM 2中，我们将研究功能后果，即UCP-1产生热量对局部淋巴运输的损失，包括对心血管疾病的影响分析，考虑到淋巴管会介导胆固醇从主动脉壁移动。