Novel approached to prevent diet-induced obesity via lacteal junctions

通过乳腺连接预防饮食引起的肥胖的新方法

• 批准号: 10394841
• 负责人: Anne Christine Eichmann
• 金额: $ 37.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394841
• 关键词: Address; Atherosclerosis; Biological; Biology; Blood Circulation; Cardiovascular Diseases; Cells; Chronic; Chylomicrons; Clinical; Data; Diet; Dietary Fats; Disease; Drainage procedure; Endothelium; Event; Fluid Balance; Functional disorder; Genetic; Genetic Models; Glaucoma; Goals; Growth Factor Receptors; Health; Immune; Inflammation; Inflammatory; Intestines; KDR gene; Knowledge; Lead; Lipids; Lymph; Lymphatic; Lymphatic Capillaries; Lymphatic Diseases; Lymphatic function; Lymphedema; Mediating; Metabolic Diseases; Molecular; Mus; Myocarditis; Nerve Degeneration; Neurodegenerative Disorders; Obesity; Pathway interactions; Pharmacology; Public Health; RHOA gene; ROCK1 gene; Regulation; Resistance; Resolution; Role; Signal Transduction; Small Intestines; System; Testing; Therapeutic Uses; Tissues; Vascular Endothelial Growth Factors; Veins; absorption; base; diet-induced obesity; experimental study; improved; in vivo; lacteal; loss of function; lymphatic drainage; lymphatic dysfunction; lymphatic vessel; macromolecule; mouse model; novel; novel strategies; obesity management; postnatal; prevent; receptor function; therapeutic target; trafficking; uptake

Project Summary Lymphatic vessels control fluid homeostasis and immune cell circulation in all body tissues, and lipid absorption in the small intestine. Their dysfunction is implicated in cardiovascular, metabolic and neurodegenerative disease. Normal lymphatic function requires a division of labor between terminal lymphatic capillaries that uptake lymph via open button junctions, and collectors that transport lymph to the veins, which have tighter zipper junctions. We here address the role of LEC button and zipper junctions in health and disease, with the hypothesis that LEC junction manipulation offers novel opportunities in clinical settings. We have shown that zippering of intestinal lacteals prevents chylomicron absorption and renders mice resistant to diet-induced obesity, prompting us to investigate molecular mechanisms inducing formation of buttons and zippers and test their implication in lipid uptake, obesity and inflammation. Collectively, the proposed studies will elucidate an as yet understudied aspect of endothelial biology and identify molecular mechanisms and novel approaches based on this knowledge that could be useful to reduce obesity via zipper formation and may be effective in diseases associated with lymphatic dysfunction via buttons.

项目摘要 淋巴管控制所有身体组织中的流体稳态和免疫细胞循环，并且脂质 在小肠中吸收。他们的功能障碍与心血管、代谢和 神经退行性疾病正常的淋巴功能需要终端之间的分工 毛细淋巴管通过开放的纽扣连接吸收淋巴液，收集器将淋巴液运送到 静脉，有更紧密的拉链连接。我们在这里解决LEC按钮和拉链连接的作用， 健康和疾病，假设LEC连接操作提供了新的机会，在临床 设置.我们已经证明，肠道乳糜管的拉链化可以阻止乳糜微粒的吸收， 小鼠抵抗饮食诱导的肥胖，促使我们研究诱导形成的分子机制 并测试它们在脂质摄取、肥胖和炎症中的意义。统称 提出的研究将阐明内皮生物学尚未充分研究的方面，并鉴定分子生物学。 基于这一知识的机制和新方法可能有助于通过以下途径减少肥胖： 拉链的形成，并可能有效的疾病与淋巴功能障碍通过按钮。