Molecular Mechanisms Controlling Lymphatic Vascular Function in Health and Disease

健康和疾病中控制淋巴血管功能的分子机制

基本信息

批准号：
10467468
负责人：
Hong Chen
金额：
$ 92.84万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-05 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467468
关键词：
ATAC-seq Adaptor Signaling Protein Adult Affect Bioenergetics Blood Vessels Cardiovascular Diseases Cells Data Development Diabetes Mellitus Diabetic Angiopathies Disease Edema Epigenetic Process Event FOXC2 gene Fluid Balance Functional disorder Funding Gene Expression Genes Genetic Models Goals Health Heart Diseases Heterozygote Homeostasis Human Impairment In Vitro Intestines Knowledge Light Link Lipids Literature Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic System Lymphatic function Lymphedema Metabolic Metabolic Control Metabolic Diseases Metabolism MicroRNAs Mission Molecular Morbidity - disease rate Mus Myocardial Infarction Natural regeneration Near-infrared optical imaging Obesity Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Play Production RNA Recovery Regulation Regulator Genes Resolution Role Signal Transduction Skin wound healing Stimulus Stroke System Tail Testing Therapeutic Tissue Sample Tissues United States National Institutes of Health VEGFC gene Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 Vascular System attenuation chromatin isolation by RNA purification sequencing combat diabetic diet-induced obesity epsin functional restoration gain of function heart function improved in vivo injured innovation loss of function lymphatic circulation lymphatic development lymphatic drainage lymphatic dysfunction lymphatic vasculature lymphatic vessel mortality mouse model new therapeutic target novel regenerative restoration single-cell RNA sequencing targeted treatment therapeutic evaluation therapeutic target transcription factor treatment strategy uptake

项目摘要

PROJECT SUMMARY/ABSTRACT The lymphatic vascular system controls tissue fluid homeostasis and intestinal lipid uptake. Proper lymphatic function positively correlates with favorable outcomes for patients with cardiovascular and metabolic disorders, which accentuates the importance of this system in maintaining systemic homeostasis. Our long-term goal is to uncover molecular mechanisms and critical regulators that govern lymphatic function in health and disease, with the hope of offering new therapeutic targets to combat cardiovascular and metabolic diseases. In the previous funding period, we discovered that the Forkhead Box C2 (Foxc2) transcription factor antagonizes vascular endothelial growth factor receptor 3 (VEGFR3) signaling by inducing the expression of epsins; endocytic adaptor proteins critical for VEGFR3 degradation and vascular endothelial growth factor C (VEGF-C) signal attenuation in lymphatic endothelial cells (LECs). We also discovered that the Forkhead Box C2 transcription factor (Foxc2) was an important regulator of obesity and that restoration of lymphatic function was a potential strategy to treat metabolic diseases. As a result, in this renewal application, we sought to identify and study additional regulatory molecules of lymphatic function. We determined that the micro-ribonucleic acid miR-22 regulates lymphatic function in normal and diseased conditions. Despite its prominence in governing lymphatic pathophysiology, little is known about the role that miR-22 plays in regulating the function of this vascular system. Consequently, we generated novel, inducible lymphatic endothelial cell (LEC)-specific miR-22 loss-of-function mice and discovered that the deficiency of this molecule dramatically increased developmental lymphangiogenesis and increased the expression of the master regulator of lymphatic differentiation and fate determination Prox1 as well as fortifying VEGF-C/VEGFR3 signaling and increasing the expression of metabolic regulatory genes. Therefore, our central hypothesis is that lymphatic miR-22 represses Prox1, constrains VEGFR3 signaling, and stymies energy production by suppressing metabolic programming. Conversely, loss of lymphatic miR-22 elevates Prox1 expression, VEGFR-3 signaling, and metabolic bioenergetics; thereby, mending impaired lymphangiogenesis and lymphatic function in cardiovascular and metabolic disorders. To test our hypothesis and determine how miR-22 inhibition exerts a pro-lymphangiogenic stimulus to ameliorate cardiovascular and metabolic disease, we propose the following related, but independent, Specific Aims: 1) to determine the role of miR-22 in governing metabolic programming and VEGFR3 signaling, 2) to determine molecular mechanisms by which miR-22 governs lymphatic function in the adult, and 3) to determine the therapeutic potential of targeting miR-22 and epsins in lymphatic systems. Our findings will identify novel molecular mechanisms underlying metabolic regulation and signaling to drive reparative and regenerative lymphangiogenesis. We anticipate that therapies targeting miR-22 or epsins may be valuable for restoring the injured lymphatic vasculature to treat cardiovascular and metabolic diseases.

项目概要/摘要淋巴血管系统控制组织液稳态和肠道脂质摄取。适当的淋巴功能与心血管和代谢疾病患者的良好结局呈正相关，这强调了该系统在维持系统稳态方面的重要性。我们的长期目标是揭示控制健康和疾病中淋巴功能的分子机制和关键调节因子，希望为对抗心血管和代谢疾病提供新的治疗靶点。在在之前的资助期间，我们发现 Forkhead Box C2 (Foxc2) 转录因子拮抗通过诱导 Epsins 的表达来调节血管内皮生长因子受体 3 (VEGFR3) 信号传导；内吞衔接蛋白对于 VEGFR3 降解和血管内皮生长因子 C (VEGF-C) 至关重要淋巴内皮细胞（LEC）中的信号衰减。我们还发现叉头盒 C2 转录因子（Foxc2）是肥胖的重要调节因子，淋巴功能的恢复是肥胖的重要调节因素。治疗代谢疾病的潜在策略。因此，在这次续展申请中，我们试图确定并研究淋巴功能的其他调节分子。我们确定微核糖核酸 miR-22 在正常和患病条件下调节淋巴功能。尽管其在执政方面的突出地位淋巴病理生理学方面，人们对 miR-22 在调节淋巴病理生理学功能中的作用知之甚少。血管系统。因此，我们生成了新型、可诱导的淋巴内皮细胞 (LEC) 特异性 miR-22 功能丧失小鼠，发现该分子的缺陷显着增加了发育淋巴管生成并增加淋巴分化和命运的主调节因子的表达测定 Prox1 以及强化 VEGF-C/VEGFR3 信号传导并增加代谢调节基因。因此，我们的中心假设是淋巴 miR-22 抑制 Prox1，限制 VEGFR3 信号传导，并通过抑制代谢程序来阻碍能量产生。相反，淋巴 miR-22 的缺失会升高 Prox1 表达、VEGFR-3 信号传导和代谢生物能量学；因此，修复心血管和心血管系统中受损的淋巴管生成和淋巴功能代谢紊乱。检验我们的假设并确定 miR-22 抑制如何发挥促淋巴管生成作用刺激改善心血管和代谢疾病，我们提出以下相关但独立的具体目标：1) 确定 miR-22 在控制代谢编程中的作用和 VEGFR3 信号转导，2) 确定 miR-22 控制淋巴功能的分子机制成人，3) 确定靶向淋巴系统中 miR-22 和 Epsins 的治疗潜力。我们的研究结果将确定代谢调节和信号驱动的新分子机制修复性和再生性淋巴管生成。我们预计靶向 miR-22 或 Epsins 的疗法可能对于恢复受损的淋巴管系统以治疗心血管和代谢疾病具有重要价值。