Mechanistic bases of vessel diameter regulation by Plexind1 - Resubmission

项目摘要 血管必须正确成形和放置，并具有具有特征性的分层组织。 和不同的口径来执行其重要的循环功能。特别是血管口径是主要的 血流特性的决定因素。因此，管腔形态测量学的异常扰乱了血液循环 降低心血管健康。我们发现，脑信号蛋白-Plexind 1（Sema-Plxnd 1）信号，已知为 它在引导脉管系统的解剖学模式中的作用，在 确定轴向中线血管（身体的主要动脉和静脉）的口径。我们的目标是 如下(1)为了确定Plxnd 1及其Sema 3配体和 血流调节这些血管的口径。(2)确定Plxnd 1依赖性血管的结构基础 口径大小以及Sema和流动力作为Plxnd 1表达调节剂的作用，顶端基底靶向， 和流动机械感测活性。我们将使用斑马鱼作为我们的主要模型系统， 在体内研究血管发育、功能和信号传导的实验优势。我们还将 用小鼠进行实验，以确定受体的新作用是否在哺乳动物中是保守的。最后为 进一步阐明Sema配体和循环力如何调节丛蛋白D1的表达，定位， 功能，我们将在可调流动条件下进行人类内皮细胞系统的研究。

PROJECT SUMMARY Blood vessels must be properly shaped and placed and have a hierarchical organization with characteristic and distinct calibers to perform their vital circulatory function. In particular, vascular caliber is the primary determinant of blood flow properties. Thus, abnormalities in luminal morphometry disrupt blood circulation and decrease cardiovascular health. We found that Semaphorin-Plexind1 (Sema-Plxnd1) signaling, known for its role in guiding the anatomical patterning of the vasculature, plays a novel blood flow-dependent role in determining the caliber of the axial midline vessels (the major artery and vein of the body). Our aims are as follows. (1) To define the signaling pathways and cellular mechanisms by which Plxnd1, its Sema3 ligands, and blood flow regulate the caliber of these vessels. (2) To define the structural bases of Plxnd1-dependent vessel caliber sizing and the role of Semas and flow forces as modulators of Plxnd1 expression, apicobasal targeting, and flow mechanosensing activity. We will use zebrafish as our primary model system to exploit its unique experimental advantages for studying vascular development, function, and signaling in vivo. We will also perform experiments with mice to determine if the receptor's novel role is conserved in mammals. Finally, to further illuminate how Sema ligands and circulatory forces modulate Plexin-D1 expression, localization, and function, we will perform studies with human endothelial cell systems under tunable flow conditions.