Flow regulation of the Alk1/Eng pathway in vascular homeostasis and disease

Alk1/Eng 通路在血管稳态和疾病中的流量调节

基本信息

批准号：
10718429
负责人：
Anne Christine Eichmann
金额：
$ 77.56万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718429
关键词：
Address Adult Arteries Arteriovenous malformation Binding Biological Blood Vessels Blood flow CRISPR screen Cell Cycle Arrest Cell Surface Receptors Complex Coronary Data Development Diameter Disease Embryo Embryonic Development Endoglin Endothelial Cells Failure Gene Expression Genes Genetic Hereditary hemorrhagic telangiectasia Homeostasis Human Impairment Inflammatory KDR gene Knowledge Life Ligands Link Liquid substance Mediating Mediator Molecular Mus PIK3CG gene Pathologic Pathway interactions Patients Perfusion Pericytes Peripheral arterial disease Physiological Piezo 1 ion channel Prevention Regulation Reporting Role Sampling Signal Pathway Signal Transduction Testing Tissues Vascular Endothelial Cell Vascular remodeling Zebrafish hemodynamics improved improved outcome in vivo inhibitor insight loss of function malformation mechanotransduction mitochondrial metabolism mouse model mutant novel programs receptor recruit response shear stress single-cell RNA sequencing therapeutic evaluation therapeutic target whole genome

项目摘要

PROJECT SUMMARY Fluid shear stress-dependent vessel remodeling is an essential regulatory mechanism in embryonic development and in adult vascular homeostasis where it optimizes blood flow to target tissues. Conversely, un- or mis-regulated remodeling results in vascular malformations, while poor remodeling is a key aspect of blood flow restriction in coronary and periphery artery disease. Our preliminary data reveal the existence of a regulatory network with two mutually inhibitory states, one associated with vessel stability and one with physiological outward remodeling or pathological AVM formation. These results allow us to propose a unifying hypothesis that links physiological and pathological remodeling, and suggest the existence of control points that can be manipulated to either increase or decrease vascular lumen diameter. The project aims to elucidate these regulatory mechanisms and then harness these new insights to investigate their relevance to vascular development, to identify therapeutic targets for HHT patients who suffer from excessive pathological remodeling, and identify therapeutic targets for coronary and peripheral artery disease patients where physiological remodeling is impaired. We will define the molecular basis of this novel EC shear stress mechanism, determine its biological role and develop and test therapeutic applications based on this knowledge.

项目摘要流体剪切应力依赖性血管重塑是胚胎中必不可少的调节机制发育和成年血管稳态中，它优化了向靶组织的血流。相反，不或重塑的错误调节会导致血管畸形，而较差的重塑是血液的关键方面冠状动脉和周围动脉疾病的流动限制。我们的初步数据揭示了监管的存在具有两个互抑制状态的网络，一种与血管稳定性有关，一种与生理学有关向外重塑或病理AVM形成。这些结果使我们能够提出一个统一的假设，链接生理和病理重塑，并建议存在控制点的存在操纵以增加或减少血管管腔直径。该项目旨在阐明这些监管机制，然后利用这些新见解来研究它们与血管的相关性开发，以确定患有过度病理重塑的HHT患者的治疗靶点，并确定生理学的冠状动脉和周围动脉疾病患者的治疗靶标重塑受损。我们将定义这种新型EC剪切应力机制的分子基础，确定它的生物学作用，并根据这些知识开发和测试治疗应用。