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: 10400033
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400033
• 关键词: Address; Albumins; Area; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cicatrix; Data; Developed Countries; Development; 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; Malignant Neoplasms; Massage; Methods; Molecular; Mus; Nitric Oxide; Nuclear Translocation; Pain; Palliative Care; Pathogenesis; Pathway interactions; Patients; Permeability; Persons; Physiological; 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; 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.

淋巴水肿是一种终生疾病，其特征是组织肿胀、纤维化和感染风险增加 在美国有数百万人是由淋巴液流动受损引起的，而先天性基因突变也可能导致。 淋巴水肿，乳腺癌切除淋巴结手术是发达国家最常见的原因 对人类患者淋巴管的分析显示淋巴管逆行和渗漏。 淋巴管，表明瓣膜功能障碍，目前缺乏有效的治疗淋巴水肿的方法。 恢复淋巴瓣功能并防止渗漏的靶向治疗将理想地增强淋巴液流动 然而，令人惊讶的是，人们对调节淋巴管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。 该实验室最近开发了唯一一种量化基因敲除小鼠淋巴管通透性的方法。 目前的提案将这种新的生理学方法与可诱导的、组织特异性的敲除结合起来 和转基因小鼠研究淋巴内皮连接蛋白信号传导。 范式——单个连接蛋白能够调节瓣膜发育和淋巴管 该提议的核心假设是通过连接蛋白 VE- 进行持续信号传导。 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。 通过提供响应剪切应力的持续细胞信号来进行终生瓣膜维护，并且 相同的途径可以防止过度的淋巴渗透（即渗漏）。 通过以下两个目标进行测试，研究淋巴连接蛋白的作用：目标 1 将测试是否 VE-钙粘蛋白通过将剪切应力转化为淋巴瓣膜的形成和维持来调节淋巴瓣膜的形成和维持 细胞内信号（即机械转导），目标 2 将确定是否相同 机械转导信号事件调节瓣膜和非瓣膜区域的淋巴通透性 这些目标的完成将导致针对 VE-钙粘蛋白的新策略。 信号传导以预防高危患者发生淋巴水肿。