EPHB4-RASA1 regulation of lymphatic vessel valve development and function

EPHB4-RASA1对淋巴管瓣膜发育和功能的调节

• 批准号: 10543485
• 负责人: PHILIP D KING
• 金额: $ 57.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543485
• 关键词: Adult; Apoptosis; Apoptotic; Basement membrane; Biological; Blood; Blood Circulation; Cardiovascular system; Cell Death; Cell membrane; Cells; Cessation of life; Chylothorax; Chylous Ascites; Collagen Type IV; Data; Defect; Deposition; Development; Disease; Embryo; Endoplasmic Reticulum; Eph Family Receptors; Extravasation; Functional disorder; Funding; Genes; Goals; Growth Factor Receptors; Guanosine Triphosphate; Health; Human; Immunity; Impairment; Inherited; Intercellular Fluid; Investments; Knowledge; Laboratories; Life; Lipids; Liquid substance; Lymph; Lymphatic; Lymphatic Capillaries; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic function; Lymphedema; Maintenance; Medical; Methodology; Mission; Molecular; Mus; Muscle Cells; Mutation; Outcome; Pathway interactions; Patients; Physiological; Play; Prevention therapy; Public Health; Ras Signaling Pathway; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Role; Signal Transduction; Signal Transduction Pathway; System; Testing; Tissues; United States National Institutes of Health; Vascular System; Venous; Vertebrates; adaptive immune response; biological adaptation to stress; blind; body cavity; burden of illness; cell growth; disability; experimental study; innovation; lymph flow; lymph nodes; lymphatic development; lymphatic valve; lymphatic vessel; mouse genetics; novel; novel therapeutics; vascular factor

The lymphatic vascular system plays an essential role in the transport of interstitial fluid and lipids, and in the induction of adaptive immune responses in vertebrates. Normal functioning of the lymphatic vascular system depends upon intraluminal lymphatic valves (LV) that facilitate propulsive flow of lymph fluid in collecting lymphatic vessels. Defects in LV development and function results in accumu- lation of lymph in tissues or body cavities resulting in lymphedema, chylothorax and chylous ascites. From a medical perspective, understanding the molecular mechanisms that regulate the development and function of LV is critical, yet our knowledge of these mechanisms remains limited. We have re- ported previously that RASA1, which inhibits activation of the intracellular Ras signal transduction pathway, is required for the development and maintenance of LV. In addition, others have reported that the receptor tyrosine kinase, EPHB4, is required for LV development. However, the precise mo- lecular mechanisms by which RASA1 and EPHB4 regulate LV are unknown. A long-term goal of the King laboratory is to understand the role of the Ras signaling pathway in different physiological sys- tems in health and disease. The overall objective of this application, which is consistent with this long- term goal, is to understand how RASA1 regulates the development and function of LV. Our central hypothesis is that RASA1, through physical interaction with EPHB4, promotes the export of collagen IV from LV-forming (LVF) lymphatic endothelial cells (LEC) and mature LEC for deposition in the ex- tracellular matrix core of developing and established LV leaflets respectively. The rationale for these studies is that they will inform upon the molecular mechanisms by which RASA1 and EPHB4 regulate the development and function of LV. We plan to test our central hypothesis and, thereby, attain the objective of this application by pursuing the following two specific aims: In the first aim, we will use different molecular cell biologic, mouse genetic, and physiological approaches to understand the mo- lecular mechanism by which RASA1 loss results in failed development and maintenance of LV. In the second aim, we will use similar approaches to understand the role of EPHB4 in the development of LV and the mechanisms involved. The proposed studies are innovative because of the novel method- ologies employed and the concept that an EPHB4-RASA1 axis is essential for the development and function of LV acting to export collagen IV from LVF LEC and LV LEC. The studies are significant be- cause of their potential to lead to new therapies for the prevention and treatment of LV abnormalities in humans with inherited mutations in RASA1 and EPHB4 genes.

淋巴血管系统在间质液和脂质的运输中起着至关重要的作用， 以及脊椎动物中适应性免疫反应的诱导。淋巴的正常功能 血管系统取决于腔内淋巴瓣（LV），促进推进流动 收集淋巴管的淋巴液。 LV开发和功能的缺陷导致累积 淋巴在组织或体腔中的效率，导致淋巴水肿，乳胸和thy子腹水。 从医学的角度来了解调节发展的分子机制 LV的功能至关重要，但是我们对这些机制的了解仍然有限。我们有重新 先前移植了抑制细胞内RAS信号转导激活的RASA1 途径是LV开发和维护所必需的。此外，其他人报告了 LV发育需要受体酪氨酸激酶EPHB4。但是，精确的mo- RASA1和EPHB4调节LV的腹膜机制尚不清楚。一个长期目标 国王实验室将了解RAS信号通路在不同生理系统中的作用 健康和疾病中的TEM。该应用程序的总体目标，这与这一长期相一致 术语目标是了解RASA1如何调节LV的开发和功能。我们的中心 假设是RASA1通过与EPHB4的物理互动促进了胶原蛋白的出口 IV从LV形成（LVF）淋巴内皮细胞（LEC）和成熟的LEC中，用于沉积 开发和建立的LV小叶的痕量基质核心。这些理由 研究是，他们将告知RASA1和EPHB4调节的分子机制 LV的开发和功能。我们计划检验我们的中心假设，从而实现 通过追求以下两个具体目的，该应用程序的目标：在第一个目标中，我们将使用 不同的分子细胞生物学，小鼠遗传和生理方法，以了解莫 RASA1损失导致LV的发育和维持失败的腹膜机制。在 第二个目的，我们将使用类似的方法来了解EPHB4在开发中的作用 LV和涉及的机制。拟议的研究具有创新性，因为这种新方法 - 所使用的神学以及EPHB4-RASA1轴对开发至关重要的概念 LV作用从LVF LEC和LV LEC导出胶原蛋白IV的功能。研究很重要 它们可能导致预防和治疗LV异常的新疗法的可能原因 在RASA1和EPHB4基因中具有遗传突变的人类中。