Obesity, Metabolic Syndrome, and Lymphatic Dysfunction

肥胖、代谢综合征和淋巴功能障碍

• 批准号: 10705331
• 负责人: JEROME W BRESLIN
• 金额: $ 60.12万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705331
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Attention; Bioinformatics; Communication; Coupled; Data; Deposition; Diet; Dietary Fats; Disease; Evaluation; Exposure to; Fluid Balance; Health; Healthcare Systems; Human; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Knock-out; Knowledge; Life; Life Style; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic function; Mediating; Mesentery; Metabolic; Metabolic dysfunction; Metabolic syndrome; Methods; Mission; Mitochondria; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ Donor; Outcome; Permeability; Prevalence; Proteins; Proteomics; Protocols documentation; Public Health; Pump; RNA; Rattus; Reproducibility; Research; Risk Factors; Rodent Model; Stress; Structure; Testing; Therapeutic; Tissues; Translating; United States National Institutes of Health; Visceral; Work; Zucker Rats; base; cadherin 5; cardiometabolic risk; design; dietary; disability; experimental study; human tissue; in vivo; innovation; insight; lipid transport; lymph flow; lymphatic development; lymphatic dysfunction; lymphatic pump; lymphatic vessel; mesenteric lymphatics; mouse model; new growth; novel; novel strategies; prevent; skills; transcriptomics; translational impact; virtual

The relationship between mesenteric lymphatic vessels and surrounding visceral adipose of the mesentery has received increased attention due to observations that imply that dysfunctional lymphatic vessels contribute to adipose deposition in the mesentery. While there has been much work done in rodent models of obesity and metabolic syndrome, there is virtually nothing known about how mesenteric lymphatic vessels are altered both structurally and functionally in humans with metabolic syndrome. To address this important and enormous knowledge gap, novel protocols to study human mesentery and lymphatic vessels derived from organ donors with or without metabolic syndrome have been developed and optimized. The rationale for this approach is that the findings will enable a leap forward in knowledge about the lymphatic-visceral adipose axis that is directly relevant to humans. The central hypothesis to be tested is that metabolic syndrome impairs lymphatic function and that impaired mesenteric lymphatics perpetuate metabolic dysfunction. Guided by robust preliminary data, this hypothesis will be tested in with two specific aims. Specific Aim 1 is to determine mechanisms underlying lymphatic dysfunction in obesity and metabolic syndrome. Specific Aim 2 is to determine how dysfunctional lymphatics contribute to metabolic deficits in mesenteric tissue. These aims will utilize mesenteric tissue from human organ donors, which permits the study of mesenteric lymphatic pump function, permeability, and network structure. The functional studies will be coupled to transcriptomic and proteomic approaches to identify the RNA and protein landscapes in the mesenteric adipose depots surrounding lymphatic vessels. In addition, studies of in vivo lymphatic pumping and permeability in relevant rat and mouse models will help identify causal mechanisms in the two-way communication between lymphatic vessels and visceral adipose tissue. The significance of the proposed research is that it will provide the first comprehensive analysis of human mesentery, including the protein and RNA landscapes, lymphatic vessel networks, lymphatic pump function, and lymphatic permeability that will produce novel information about how human lymphatic vessels interact with visceral adipose tissue in the context of metabolic syndrome. The proposed research is innovative because it opens a new line of investigation focusing on human mesenteric lymphatic structure and function that will provide the first large-scale evaluation of human mesenteric lymphatic pump function and permeability directly related to human health and disease.

肠系膜淋巴管与肠系膜周围内脏脂肪的关系 由于观察到功能障碍的淋巴管有助于 肠系膜脂肪沉积。虽然在肥胖和肥胖的啮齿动物模型上已经做了很多工作 代谢综合征，关于肠系膜淋巴管是如何改变的，几乎一无所知 代谢综合征患者的结构和功能。为了解决这一重要而巨大的问题 知识鸿沟--研究人体肠系膜和器官供体淋巴管的新方案 无论有没有代谢综合征，都得到了开发和优化。这种方法的基本原理是 这一发现将使人们对淋巴-内脏脂肪轴的认识实现飞跃，这是直接 与人类相关。有待检验的中心假设是代谢综合征损害淋巴功能 肠系膜淋巴管受损会使代谢功能障碍永久化。在稳健的初步数据的指导下， 这一假设将以两个具体目标进行检验。具体目标1是确定潜在的机制 肥胖和代谢综合征患者的淋巴功能障碍。具体目标2是确定功能障碍 淋巴管导致肠系膜组织的代谢缺陷。这些目标将利用来自 人体器官捐赠者，允许研究肠系膜淋巴泵功能、通透性和网络 结构。功能研究将与转录学和蛋白质组学方法相结合，以鉴定RNA 和淋巴管周围的肠系膜脂肪库中的蛋白质景观。此外，还研究了 相关大鼠和小鼠模型的体内淋巴泵和通透性将有助于确定病因 淋巴管与内脏脂肪组织双向通讯的机制。这个 这项拟议的研究的意义在于，它将提供第一个对人类肠系膜的全面分析， 包括蛋白质和RNA景观、淋巴管网络、淋巴泵功能和淋巴管 渗透性将产生关于人类淋巴管如何与内脏相互作用的新信息 代谢综合征背景下的脂肪组织。这项拟议的研究具有创新性，因为它开启了 专注于人类肠系膜淋巴结构和功能的新研究路线将提供第一个 与人类直接相关的人肠系膜淋巴泵功能和通透性的大规模评估 健康和疾病。