Cooperative Regulation of Mechanotransduction for Lymphatic Valve Development by Prox1 and Nf-kB

Prox1 和 Nf-kB 协同调节淋巴瓣发育的机械传导

• 批准号: 9927493
• 负责人: Young-Kwon Hong
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927493
• 关键词: Address; Adult; Adverse effects; Affinity; Animal Model; Binding; Binding Sites; Biochemical; Bioinformatics; Blood Vessels; Cations; Cell Differentiation process; Cells; Collaborations; Communication; Cues; DNA-Protein Interaction; Development; Drainage procedure; Drug Targeting; Embryo; Endothelial Cells; Genetic; Goals; Health; Immune; In Vitro; Inflammation; Intestines; Liquid substance; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Maintenance; Mechanics; Mediating; Modeling; Molecular; Molecular Genetics; Morphogenesis; NF-kappa B; Natural regeneration; Nuclear Translocation; Outcome; Pathway interactions; Pattern; Periodicity; Phosphorylation; Piezo 1 ion channel; Property; Protein Dephosphorylation; Proteins; Regulation; Reporting; Role; Shapes; Signal Transduction; Stains; Stimulus; Stretching; Tissues; Transducers; Up-Regulation; Vascular System; Venous; base; epigenetic regulation; fluid flow; in vivo; insight; lymph flow; lymphatic vessel; mechanotransduction; mutant; nutrient absorption; p65; programs; protein protein interaction; sensor; synaptotagmin I; trafficking; transcription factor

PROJECT SUMMARY Lymphatic valves are essential for the proper lymph flow occurring during tissue fluid drainage and transport, immune cell trafficking and nutrient absorption in the intestine. Despite their critical roles in vascular function and health, relatively little is known about the molecular mechanism that controls lymphatic valve development and maintenance. In this proposal, we aim to elucidate the mechanotransduction that incorporates the fluid flow-driven external signals into the internal genetic programs governing the valve formation and function in the lymphatic system. We have recently identified a unique fluid flow condition that could induce the signatures of the early stages of lymphatic valve development, including Prox1 upregulation, an initial hallmark of valvular endothelial cell specification that was not attainable by other reported flow conditions. Imposing mechanical cell stretching, this experimental setup induces p65 nuclear translocation, Prox1 upregulation and dephosphorylation, and their functional collaboration through both protein-protein interaction and binding site sharing. These observations have led us to hypothesize that Prox1 and p65 cooperatively control a yet uncharacterized valve-forming mechanotransduction pathway in lymphatic compartment, and possibly conserved in venous vessels as well. We propose that our experimental flow condition will allow us to address this hypothesis by offering a unique opportunity to dissect the mechanotransduction. In addition, we will confirm the regulation and function of the essential physical, molecular and genetic constituents of the mechanotransduction using various animal models. The outcome will not only advance our current understanding of lymphatic valve formation and function, but also provide fundamental insights into the mechanisms underlying the flow-regulated vascular development and function.

项目概要 淋巴瓣对于组织液引流和运输过程中淋巴液的正常流动至关重要， 肠道内的免疫细胞运输和营养吸收。尽管它们在血管功能中发挥着关键作用 和健康方面，人们对控制淋巴瓣发育的分子机制知之甚少 和维护。在本提案中，我们的目标是阐明包含流体的力传导 流动驱动的外部信号进入内部遗传程序，控制瓣膜的形成和功能 淋巴系统。我们最近发现了一种独特的流体流动条件，可以引起以下特征： 淋巴瓣发育的早期阶段，包括 Prox1 上调，这是瓣膜的最初标志 其他报道的流动条件无法实现的内皮细胞规格。令人印象深刻的机械 细胞拉伸，该实验设置诱导 p65 核易位、Prox1 上调和 去磷酸化，以及它们通过蛋白质-蛋白质相互作用和结合位点的功能协作 分享。这些观察结果使我们推测 Prox1 和 p65 协同控制 淋巴室中未表征的瓣膜形成机械传导途径，并且可能 也保存在静脉血管中。我们建议我们的实验流动条件将使我们能够解决 这一假设提供了一个独特的机会来剖析机械传导。此外，我们将 确认基本物理、分子和遗传成分的调节和功能 使用各种动物模型进行机械转导。结果不仅将推进我们目前的 了解淋巴瓣的形成和功能，还提供了对淋巴瓣膜的基本见解 流量调节血管发育和功能的潜在机制。