Mechanistic bases of vessel diameter regulation by Plexind1 - Resubmission

Plexind1 调节血管直径的机制基础 - 重新提交

基本信息

批准号：
10522665
负责人：
Jesús Torres-Vázquez
金额：
$ 76.84万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2022-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522665
关键词：
3-Dimensional Address Adherent Culture Adult Anatomy Animals Apical Area Arteries Atherosclerosis Binding Biological Models Blood Circulation Blood Vessels Blood flow Caliber Cardiac Cardiac Myocytes Cell surface Cessation of life Characteristics Data Defect Development Dissection Embryo Endothelial Cells Endothelium Ensure Excision Exhibits Fishes Genes Genetic Genetic Transcription Heart Hemorrhage Hereditary hemorrhagic telangiectasia Human In Vitro Inherited Knowledge Life Ligands Mammals Measures Mediating Messenger RNA Molecular Mus Mutation Myocardial Organ Pattern Play Process Property Proteins Regulation Reporter Role Semaphorins Side Signal Pathway Signal Transduction Sum System Testing Tissues Trees Troponin T Tube Vascular Diseases Veins Ventricular Zebrafish base cardiovascular health cerebral cavernous malformations experimental study in vivo mechanotransduction morphometry mutant novel overexpression plexin receptor shear stress

项目摘要

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.

项目概要血管必须具有适当的形状和位置，并具有具有特征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，血管口径是首要的血流特性的决定因素。因此，管腔形态测量的异常会扰乱血液循环并降低心血管健康。我们发现 Semaphorin-Plexind1 (Sema-Plxnd1) 信号传导，以它在指导脉管系统的解剖模式中发挥作用，在以下方面发挥着新的血流依赖性作用确定轴向中线血管（身体的主要动脉和静脉）的口径。我们的目标是接下来。 (1) 定义 Plxnd1、其 Sema3 配体和血流调节这些血管的口径。 (2) 定义Plxnd1依赖性血管的结构基础口径大小以及 Semas 和流动力作为 Plxnd1 表达、apicobasal 靶向调节剂的作用，和流动机械传感活动。我们将使用斑马鱼作为我们的主要模型系统来利用其独特的研究体内血管发育、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在哺乳动物中是否保守。最后，为了进一步阐明 Sema 配体和循环力如何调节 Plexin-D1 表达、定位和功能，我们将在可调流量条件下对人内皮细胞系统进行研究。