Lymphatic Endothelial Permeability as a Regulator of Mesenteric Adipose Depositio

描述(申请人提供)：肥胖已成为一个全球健康问题，目前影响约35%的美国人口，估计每年的医疗费用在860亿至2100亿美元之间。与肥胖相关的慢性炎症往往会导致胰岛素抵抗，最终导致2型糖尿病。腹部脂肪尤其与 高血压、动脉粥样硬化、中风和癌症的心血管风险增加。令人惊讶的是，人们对导致腹部脂肪沉积的最初机制知之甚少。有趣的是，膳食脂肪主要被微绒毛中的毛细淋巴管吸收，并被输送到通常被脂肪组织包围的肠系膜收集淋巴管。尽管淋巴管渗漏和脂肪组织沉积之间的关系由来已久，但还没有研究确定当淋巴管没有遗传变形或畸形时，病理生理学渗漏是否会导致脂肪沉积(即正常发育但渗漏的淋巴管是否会导致脂肪沉积)。这一领域研究的匮乏源于缺乏一种测量淋巴对溶质渗透性的方法。我最近开发了一种定量方法，首次能够快速、可重复地测量收集淋巴管的渗透性，并允许进行药物操作。此外，我将这种方法与遗传小鼠模型相结合，以确定淋巴通透性的机械调节因素(例如一氧化氮、组胺)，并证明从肥胖的瘦素受体基因敲除小鼠收集淋巴管具有显著的通透性升高。这项研究的目的是确定淋巴管通透性在肠系膜脂肪沉积中的作用，包括研究与脂肪组织和树突状细胞的串扰。在这项工作的指导阶段(目标1)，我将通过使用可诱导的小鼠模型来删除内皮屏障功能的关键调节因子�-连环蛋白，从而创建一个渗漏的淋巴管系统，该调节因子具体来自淋巴管而不是血管。这个模型将被用来测试正常图案淋巴管的渗漏是否足以导致显著的肠系膜脂肪沉积。在独立阶段，我将确定炎性肠系膜脂肪组织如何增加收集淋巴管的通透性，以及渗透到脂肪组织的T细胞是否负有责任(目标2)。 此外，我还将确定位于淋巴管壁的树突状细胞是否可以阻止淋巴管通透性的增加，还是可以提高淋巴管的通透性(目标3)。淋巴通透性升高作为脂肪沉积调节剂的新概念将提高对与脂肪组织相关的慢性炎症性疾病(如克罗恩病、淋巴水肿)的理解。最终，加强淋巴管内皮细胞屏障的治疗靶点可能提供一种新的方法来防止肥胖患者的脂肪沉积，从而减少相关心血管疾病的发生率。

DESCRIPTION (provided by applicant): Obesity has become a global health problem and currently affects ~35% of the US population, with estimated medical costs ranging between $86 and $210 billion per year. Chronic inflammation associated with obesity often leads to insulin resistance and, eventually, type-2 diabetes. Abdominal fat in particular is closely associated with an increased cardiovascular risk of hypertension, atherosclerosis, stroke, and cancer. Surprisingly, very little is known about the initial mechanisms leading to abdominal adipose deposition. Interestingly, dietary lipids are absorbed primarily by lymphatic capillaries in the microvilli and transported to collecting lymphatic vessels in the mesentery, which are normally surrounded by adipose tissue. Despite long- standing associations between lymphatic vessel leakage and adipose tissue deposition, no studies have been performed to determine whether pathophysiological lymphatic leakage can lead to adipose deposition when lymphatic vessels are not genetically deformed or mispatterned (i.e. whether normally developed but leaky lymphatic vessels can cause adipose deposition). The dearth of studies in this area stems from the lack of a method to measure lymphatic permeability to solute. I recently developed a quantitative method that enables rapid, repeatable measurements of collecting lymphatic vessel permeability for the first time, and permits pharmacologic manipulation. Further, I have combined this method with genetic mouse models to identify mechanistic regulators of lymphatic permeability (e.g. nitric oxide, histamine) and to demonstrate that collecting lymphatics from obese, leptin receptor knockout mice have a markedly elevated permeability. The goal of the proposed research is to determine the role of lymphatic vascular permeability in mesenteric adipose deposition, including investigating crosstalk with adipose tissue and dendritic cells. In the mentored phase of this work (Aim 1), I will create a leaky lymphatic vasculature by using an inducible mouse model to delete a crucial regulator of endothelial barrier function, �-catenin, specifically from lymphatic vessels and not blood vessels. This model will be used to test whether leakage from normally patterned lymphatic vessels is sufficient to lead to significant mesenteric adipose deposition. In the independent phase, I will then determine how inflammatory mesenteric adipose tissue increases collecting lymphatic vessel permeability and whether T-cells that infiltrate the adipose tissue are responsible (Aim 2). Additionally, I will determine whether dendritic cells residing in the lymphatic vessel wall protec against increases in lymphatic permeability, or instead elevate lymphatic permeability (Aim 3). The novel concept of elevated lymphatic permeability as a regulator of adipose deposition will improve the understanding of chronic inflammatory diseases that are associated with adipose tissue (e.g. Crohn's disease, lymphedema). Ultimately, therapeutic targets that tighten the lymphatic endothelial barrier may offer a new approach to prevent adipose deposition in obesity, thereby reducing the incidence of associated cardiovascular diseases.