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

• 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
• 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

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.

项目概要 流体剪切应力依赖性血管重塑是胚胎中重要的调节机制 发育和成人血管稳态，优化流向目标组织的血流。相反，非 或失调的重塑会导致血管畸形，而不良的重塑是血液的一个关键方面 冠状动脉和外周动脉疾病中的血流限制。我们的初步数据揭示了监管机构的存在 具有两种相互抑制状态的网络，一种与血管稳定性相关，另一种与生理相关 外向重塑或病理性 AVM 形成。这些结果使我们能够提出一个统一的假设 将生理和病理重塑联系起来，并提出可以控制的控制点的存在 操纵以增加或减少血管腔直径。该项目旨在阐明这些 调节机制，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， 并确定冠状动脉和外周动脉疾病患者的治疗靶点 重塑受到损害。我们将定义这种新型 EC 剪切应力机制的分子基础，确定 其生物学作用，并根据这些知识开发和测试治疗应用。