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Obesity, Metabolic Syndrome, and Lymphatic Dysfunction

肥胖、代谢综合征和淋巴功能障碍

基本信息

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
项目类别：
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

项目摘要

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.