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

• 批准号: 10626892
• 负责人: Hong Chen
• 金额: $ 87.07万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10626892
• 关键词: ATAC-seq; Acceleration; Adaptor Signaling Protein; Adult; Affect; Bioenergetics; Blood Vessels; Breeding; Cardiovascular Diseases; Cells; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Disease; Edema; Elderly; Epigenetic Process; Event; Fluid Balance; Functional disorder; Funding; Gene Expression; Genes; Genetic Models; Goals; Health; Heart Diseases; Heterozygote; Homeostasis; Human; Impairment; In Vitro; Intestines; Knowledge; Link; Lipids; Literature; Loss of Heterozygosity; 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; Repression; Resolution; Role; Signal Induction; Signal Transduction; Skin wound healing; Stimulus; Stroke; System; Tail; Testing; Therapeutic; Tissue Sample; Tissues; United States National Institutes of Health; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Vascular System; attenuation; combat; diabetic; diet-induced obesity; epsin; fortification; 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; restraint; single-cell RNA sequencing; targeted treatment; therapeutic evaluation; therapeutic target; transcription factor; treatment strategy; uptake

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.

项目摘要/摘要 淋巴管系统控制组织液体稳态和肠脂质摄取。适当的淋巴 功能与心血管和代谢性疾病患者的有利结局呈正相关， 这突显了该系统在维持系统性稳态方面的重要性。我们的长期目标是 发现控制健康和疾病淋巴功能的分子机制和关键调节剂， 希望提供新的治疗靶标，以打击心血管和代谢疾病。在 以前的资金期，我们发现叉子盒C2（FOXC2）转录因子对抗 血管内皮生长因子受体3（VEGFR3）信号通过诱导Epsins的表达来传导； 对于VEGFR3降解和血管内皮生长因子C（VEGF-C）至关重要的内吞衔接蛋白 淋巴内皮细胞（LEC）中的信号衰减。我们还发现叉子盒C2 转录因子（FOXC2）是肥胖的重要调节剂，淋巴功能的恢复是 治疗代谢疾病的潜在策略。结果，在此续签应用中，我们试图确定 并研究淋巴功能的其他调节分子。我们确定了微核酸酸 miR-22在正常和患病状况下调节淋巴功能。尽管它在理事中很有意义 淋巴病理生理学，对miR-22在调节其功能中的作用知之甚少 血管系统。因此，我们生成了新颖的，可诱导的淋巴内皮细胞（LEC）特异性miR-22 功能丧失的小鼠，发现该分子的不足大大增加了发育 淋巴管生成并增加了淋巴分化和命运的主要调节剂的表达 确定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， 通过抑制代谢编程来限制VEGFR3信号传导和Stymies能量产生。 相反，淋巴miR-22的丧失升高Prox1表达，VEGFR-3信号和代谢 生物能学；因此，修补了心血管和 代谢障碍。为了检验我们的假设并确定miR-22抑制如何发挥促淋巴管生成 为了改善心血管和代谢疾病的刺激，我们提出以下相关，但 独立，具体目的：1）确定miR-22在代谢编程中的作用和 VEGFR3信号传导，2）确定miR-22控制淋巴功能的分子机制 成人，以及3）确定靶向miR-22和epsins在淋巴系统中的治疗潜力。我们的 调查结果将确定代谢调节和信号传导的基本分子机制 修复性和再生淋巴管生成。我们预计针对miR-22或epsins的疗法可能 对于恢复受伤的淋巴脉管系统来治疗心血管和代谢疾病很有价值。

项目成果

Lymphatic-draining nanoparticles deliver Bay K8644 payload to lymphatic vessels and enhance their pumping function.

• DOI: 10.1126/sciadv.abq0435
• 发表时间: 2023-02-24
• 期刊: Science advances
• 影响因子: 13.6

Effect of Human Synovial Fluid From Osteoarthritis Patients and Healthy Individuals on Lymphatic Contractile Activity.

骨关节炎患者和健康个体的人体滑液对淋巴收缩活动的影响。

• DOI: 10.1115/1.4053749
• 发表时间: 2022
• 期刊: Journal of biomechanical engineering
• 作者: Michalaki,Eleftheria;Nepiyushchikh,Zhanna;Rudd,JosephineM;Bernard,FabriceC;Mukherjee,Anish;McKinney,JayM;Doan,ThanhN;Willett,NickJ;Dixon,JBrandon
• 通讯作者: Dixon,JBrandon

Multichromatic near-infrared imaging to assess interstitial lymphatic and venous uptake in vivo.

• DOI: 10.1117/1.jbo.26.12.126001
• 发表时间: 2021-12
• 期刊: Journal of biomedical optics
• 影响因子: 3.5
• 作者: Bernard FC;Kaiser J;Raval SK;Nepiyushchikh ZV;Doan TN;Willett NJ;Dixon JB
• 通讯作者: Dixon JB