LOCAL THERMOGENESIS IN LYMPHATIC VESSEL/NODE FUNCTION

描述（由申请人提供）：淋巴系统，包括淋巴管和淋巴结（LNs），至关重要地调节液体平衡，营养吸收和免疫。盲端淋巴毛细血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血管，从LNs流出和流出。由特化肌肉细胞包围的收集血管控制淋巴系统中淋巴运输的速率和大小。集束血管和淋巴结都不可避免地被脂肪组织包围。有趣的是，啮齿动物突出的LNs和淋巴收集血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，从主要由白色、储存能量的单室脂肪细胞组成的特征转变为表达UCP-1的棕色多室脂肪细胞。棕色脂肪细胞通过线粒体解偶联蛋白1 （UCP-1）产生热量，而UCP-1对其产热特性至关重要。重要的是，在成年人中发现了米色脂肪组织，全身图像显示，成年人的棕色脂肪库与经典的LNs位置共地，类似于小鼠的米色皮下库，不可避免地包裹着LNs。事实上，最近的组织学分析证实，在人类中含有棕色脂肪细胞的脂肪库与LNs共定位，就像在小鼠中一样。人类心脏和大动脉周围也发现了米色脂肪，在老鼠身上也观察到了这一点。虽然棕色脂肪在冷应激条件下产生热量的功能得到了很好的认识，但只有少数研究解决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了维持特定功能所必需的局部产热作用？也许棕色脂肪作为产热器官的主要作用是关键，通过UCP-1诱导增加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随着温度升高而显著增加。因此，我们假设米色脂肪中的产热作用在支持淋巴系统中起着关键作用，包括通过淋巴脉管系统运输货物（如高密度脂蛋白胆固醇或抗原）和邻近淋巴结的整体功能。在目的1中，我们将研究淋巴结周围和淋巴管周围的产热是否支持淋巴运输到淋巴结并维持免疫反应，特别是在冷挑战的背景下。在目的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后果，包括考虑到淋巴血管介导胆固醇出主动脉壁的运动，对心血管疾病的影响进行分析。

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.