Regulation of Lymphatic Endothelial Cell Junction and Drainage

淋巴内皮细胞连接和引流的调节

基本信息

批准号：
10642883
负责人：
Esak Lee
金额：
$ 47.54万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642883
关键词：
3-Dimensional Alzheimer&apos s Disease Animal Model Architecture Arthritis Binding Biological Biology Biomedical Engineering Biophysics Blood Vessels Boston Brain Cell Culture Techniques Cells Clinical Research Collaborations Complex Development Dietary Fats Disease Drainage procedure Exhibits Experimental Models Fibronectins Fibrosis Fluid Balance Glaucoma Goals Homeostasis Human ITGA5 gene Immune System Diseases Immunity Immunologist In Vitro Inflammation Inflammatory Inflammatory Response Intercellular Fluid Intercellular Junctions Ligands Liquid substance Lymph Lymphatic Lymphatic Diseases Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic System Lymphatic function Lymphedema Malignant Neoplasms Mediating Meningeal lymphatic system Metabolic Diseases Modeling Morphogenesis Morphology Mus Neurodegenerative Disorders Neurons Obesity Organ Outcome Pediatric Hospitals Pericytes Permeability Physiological Protein Kinase ROCK1 gene Regulation Research Personnel Role Signal Transduction Small Intestines Structure Tissues Treatment Efficacy Universities Vascular System drug candidate human disease in vitro Model in vivo in vivo Model inhibitor lacteal lymph nodes lymphatic drainage lymphatic dysfunction lymphatic vessel rho screening therapeutic evaluation three-dimensional modeling tool two-dimensional uptake wasting

项目摘要

PROJECT SUMMARY Lymphatic vessel (LV) differentiation, development, and morphogenesis are central in maintaining fluid homeostasis, regulating host immunity, and transporting dietary fat and neuronal waste. All these functions are governed by lymphatic drainage, a transport of interstitial fluid into the lymphatic system through the initial LVs and collecting LVs. The initial LVs show permeable button-like junction morphology and are ready to uptake interstitial fluid; by contrast, the collecting LVs are less permeable with zipper-like junction structure, so that the collecting LVs transport ‘lymph’ to lymph nodes without leaking. Impaired lymphatic drainage contributes to many human diseases, such as lymphedema, immune dysfunction, fibrosis, obesity, cancer, and Alzheimer’s disease. While little is known about why LVs become dysfunctional, clinical studies reveal that inflammation is one of the leading contributors to the lymphatic dysfunction. Although dysfunctional collecting LVs has been extensively studied, how inflammation impacts initial LV development and morphogenesis is unclear, because in our current experimental models, including animal models, we often cannot decouple multifactorial inflammatory factors in the lymphatic endothelium. Since two-dimensional cell culture has failed to recapitulate three-dimensional (3D) tissue architecture of lymphatics, researchers have developed 3D in vitro models of LVs, demonstrating lymphatic sprouting, lymphatic network formation, and LV interactions with other cells. However, these previous models have not created 3D lymphatic structure with specialized LEC junction development enabling controlled fluid drainage through the button-like junctions and physiological inflammatory response. In this proposal, we will use a bioengineered in vitro 3D lymphatic vascular system, exhibiting button-like junction morphogenesis of the LVs and fluid drainage to understand the regulation of LEC junction and drainage by focusing on ROCK1/2 and integrin α5 signaling. In Aim 1, we will examine the roles of ROCKs in LEC junction and drainage. Next, we will scrutinize the mechanisms of ROCKs-mediated junction zippering in LECs. In Aim 2, we will study integrin α5 mediated regulation of LEC junction and lymphatic drainage. We will then determine signal transduction through ROCKs and integrin α5 and evaluate therapeutic efficacy of targeting ROCKs and integrin α5 in lymphatic dysfunction and inflammation models in vivo. In summary, we will use a bioengineered model of 3D lymphatic vessels and fluid transport to provide an understanding of lymphatic drainage in normal and inflammatory conditions.

项目概要淋巴管 (LV) 分化、发育和形态发生对于维持液体至关重要体内平衡、调节宿主免疫力以及运输膳食脂肪和神经元废物所有这些功能。受淋巴引流控制，即间质液通过最初的淋巴管输送到淋巴系统 LV 和收集 LV 最初的 LV 显示可渗透的纽扣状连接形态，并准备好。吸收间质液；相比之下，集合左心室具有拉链状连接结构，渗透性较差，以便收集左心室将“淋巴”输送至淋巴结，而不会损害淋巴引流。导致许多人类疾病，如淋巴水肿、免疫功能障碍、纤维化、肥胖、癌症、和阿尔茨海默氏病虽然人们对左心室功能失调的原因知之甚少，但临床研究表明。炎症是淋巴功能障碍的主要原因之一。收集 LV 已被广泛研究，炎症如何影响 LV 的初始发育和形态发生尚不清楚，因为在我们目前的实验模型，包括动物模型中，我们经常由于二维细胞，不能解耦淋巴管内皮中的多因素炎症因子。研究人员发现，培养物未能重现淋巴管的三维 (3D) 组织结构开发了 LV 的 3D 体外模型，展示了淋巴萌芽、淋巴网络形成以及 LV 与其他细胞的相互作用然而，这些先前的模型尚未创建 3D 淋巴结构。具有专门的 LEC 连接开发，可通过按钮状控制液体排出在本提案中，我们将使用生物工程体外 3D。淋巴管系统，表现出左心室的纽扣状连接形态发生和液体引流通过关注 ROCK1/2 和整合素 α5 信号传导来了解 LEC 连接和引流的调节。在目标 1 中，我们将研究 ROCK 在 LEC 连接和排水中的作用。 ROCK 介导的 LEC 中连接拉链的机制在目标 2 中，我们将研究整合素 α5 介导的。 LEC 连接和淋巴引流的调节然后我们将通过以下方式确定信号转导。 ROCKs 和整合素 α5 并评估淋巴管中靶向 ROCKs 和整合素 α5 的治疗效果总之，我们将使用 3D 淋巴管的生物工程模型。血管和液体运输，以了解正常和炎症的淋巴引流状况。