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 由于观察表明功能失调的淋巴管会导致 肠系膜内脂肪沉积。尽管在肥胖和肥胖的啮齿动物模型方面已经做了很多工作 代谢综合征，对于肠系膜淋巴管如何改变几乎一无所知 患有代谢综合征的人类的结构和功能。为了解决这个重要而巨大的问题 知识差距，研究来自器官捐赠者的人类肠系膜和淋巴管的新方案 患有或不患有代谢综合症的药物已经被开发和优化。这种方法的基本原理是 这些发现将使有关淋巴-内脏脂肪轴的知识取得飞跃，该轴直接关系到淋巴-内脏脂肪轴。 与人类相关。要测试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导致代谢功能障碍持续存在。在可靠的初步数据的指导下， 该假设将通过两个具体目标进行检验。具体目标 1 是确定潜在机制 肥胖和代谢综合征中的淋巴功能障碍。具体目标 2 是确定功能失调的程度 淋巴管导致肠系膜组织代谢缺陷。这些目标将利用来自 人体器官捐献者，可用于研究肠系膜淋巴泵功能、渗透性和网络 结构。功能研究将与转录组学和蛋白质组学方法相结合来鉴定 RNA 以及淋巴管周围肠系膜脂肪库中的蛋白质景观。此外，研究 相关大鼠和小鼠模型中的体内淋巴泵和渗透性将有助于确定因果关系 淋巴管和内脏脂肪组织之间双向通讯的机制。这 这项研究的意义在于它将首次对人类肠系膜进行全面分析， 包括蛋白质和 RNA 景观、淋巴管网络、淋巴泵功能和淋巴管 渗透性将产生有关人体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。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 大规模评价人体肠系膜淋巴泵功能和通透性，与人体直接相关 健康和疾病。