Pathways Regulating Lymphatic Vessel Permeability and Valve Formation

调节淋巴管渗透性和瓣膜形成的途径

• 批准号: 10599157
• 负责人: Joshua Paul SCALLAN
• 金额: $ 42.92万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-24 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599157
• 关键词: Address; Albumins; Area; Biological Assay; Blood Vessels; Breeding; Cancer Survivor; Cardiovascular Diseases; Cicatrix; Data; Developed Countries; Development; Diabetes Mellitus; Disease; Edema; Event; Excision; Extravasation; FOXC2 gene; Fibrosis; Functional disorder; Gene Mutation; Genetic; Growth; Health; Human; Impairment; Infection; KDR gene; Knock-out; Knockout Mice; Life; Liquid substance; Lymph; Lymphatic; Lymphatic Endothelium; Lymphedema; Maintenance; Massage; Methods; Molecular; Mus; Nitric Oxide; Nuclear Translocation; Obesity; Pain; Palliative Care; Pathogenesis; Pathway interactions; Patients; Permeability; Persons; Physiological; Predisposition; Proteins; Publishing; Risk; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Structure; Swelling; Tamoxifen; Testing; Time; Tissues; Transgenic Mice; Work; arm; beta catenin; cadherin 5; cancer surgery; draining lymph node; effective therapy; experimental study; hypercholesterolemia; infection risk; innovation; lymph flow; lymph nodes; lymphatic imaging; lymphatic valve; lymphatic vasculature; lymphatic vessel; malignant breast neoplasm; mechanotransduction; new therapeutic target; preservation; prevent; response; shear stress; targeted treatment; therapeutic target; transcription factor

Lymphedema is a lifelong disease characterized by tissue swelling, fibrosis, and increased risk of infections for millions of people in the US and is caused by impaired lymph flow. While congenital gene mutations can cause lymphedema, breast cancer surgery to remove lymph nodes is the most common cause in developed countries. Analyses of lymphatic vessels in human patients have revealed retrograde lymph flow and leaky lymphatic vessels, indicating valve dysfunction. An effective treatment for lymphedema is currently lacking, but targeted therapies to restore lymphatic valve function and prevent leakage would ideally enhance lymph flow in these patients. However, surprisingly little is known about the molecules or mechanisms regulating lymphatic vessel permeability because no methods existed to quantify lymphatic permeability. To address this gap, our lab recently developed the only approach to quantify the permeability of lymphatic vessels from knockout mice. The current proposal has combined this new physiological approach with inducible, tissue-specific knockout and transgenic mice to investigate lymphatic endothelial junction protein signaling. Our results suggest a new paradigm – that a single junction protein is capable of regulating both valve development and lymphatic vessel permeability. The central hypothesis of this proposal is that constant signaling through the junction protein, VE- cadherin, maintains normal valve structure and lymphatic barrier function. Our findings show that VE-cadherin is required for lifelong valve maintenance by providing persistent cell signals in response to shear stress, and the same pathway prevents excessive lymphatic permeability (i.e. leakage). The central hypothesis will be tested by the following two aims investigating the role of lymphatic junction proteins: Aim 1 will test whether VE-cadherin regulates lymphatic valve formation and maintenance by transducing shear stress into intracellular signals (i.e. mechanotransduction), and Aim 2 will determine whether the same mechanotransduction signaling events regulate lymphatic permeability in the valve and non-valve areas of lymphatic collecting vessels. The completion of these aims will lead to new strategies to target VE-cadherin signaling to prevent the development of lymphedema in at-risk patients.

淋巴水肿是一种终身性疾病，其特征在于组织肿胀、纤维化和感染的风险增加。 在美国有数百万人，是由淋巴液流动受损引起的。虽然先天性基因突变会导致 乳腺癌手术切除淋巴结是最常见的原因，在发达国家 国家对人类患者的淋巴管的分析揭示了逆行淋巴流和渗漏。 淋巴管表明瓣膜功能障碍目前缺乏有效的治疗水肿的方法，但 恢复淋巴瓣功能和防止渗漏的靶向治疗将理想地增强淋巴流动， 这些病人。然而，令人惊讶的是，人们对调节淋巴细胞增殖的分子或机制知之甚少。 血管通透性，因为没有方法可以量化淋巴通透性。为了弥补这一差距，我们 实验室最近开发了唯一的方法来量化基因敲除小鼠淋巴管的渗透性。 目前的建议结合了这种新的生理方法与诱导，组织特异性敲除 和转基因小鼠来研究淋巴管内皮连接蛋白信号传导。我们的研究结果表明， 范例-单个连接蛋白能够调节瓣膜发育和淋巴管 磁导率该提议的中心假设是，通过连接蛋白VE-1的恒定信号传导， 钙粘蛋白，维持正常的瓣膜结构和淋巴屏障功能。我们的研究结果表明，VE-钙粘蛋白 通过响应剪切应力提供持续的细胞信号， 相同的途径可以防止过度的淋巴渗透性（即渗漏）。核心假设是 通过以下两个目标进行测试，研究淋巴结蛋白的作用：目标1将测试是否 VE-钙粘蛋白通过将切应力转换为 细胞内信号（即机械转导），Aim 2将确定是否相同 机械转导信号传导事件调节淋巴管的瓣膜和非瓣膜区域的淋巴渗透性， 淋巴集合管这些目标的实现将导致针对VE-钙粘蛋白的新策略 信号以防止高危患者发生水肿。

项目成果

Endothelial Nitric Oxide Synthase Regulates Lymphatic Valve Specification By Controlling β - catenin Signaling During Embryogenesis.

内皮一氧化氮合酶通过控制胚胎发生过程中的β-连环蛋白信号传导来调节淋巴瓣膜规格。

• DOI: 10.1101/2023.04.10.536303
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Iyer,Drishya;Mastrogiacomo,Diandra;Li,Kunyu;Banerjee,Richa;Yang,Ying;Scallan,JoshuaP
• 通讯作者: Scallan,JoshuaP

VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes.

• DOI: 10.3389/fphys.2021.687563
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Jannaway M;Scallan JP
• 通讯作者: Scallan JP