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Endothelial Mechanotransduction in Thoracic Aneurysm Formation and Progression

胸动脉瘤形成和进展中的内皮力传导

基本信息

批准号：
10378126
负责人：
Martin A Schwartz
金额：
$ 44.29万
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：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378126
关键词：
Abdomen Affect Aneurysm Angiotensin II Receptor Angiotensin Receptor Aorta Arteries Biological Models Biology Blood Pressure Blood flow Cells Cerebrum Chest Communication Continuous Infusion Data Defect Development Dissection Endothelial Cells Endothelium Extracellular Matrix FBN1 Failure Gene Deletion Gene Expression Profile Genes Growth Human Hypertension ITGA5 gene Inflammation Inflammation Mediators Inflammatory Integrins Intervention Knock-in Mouse Lead Ligands Link Liquid substance Marfan Syndrome Mediating Mediator of activation protein Modeling Mus Mutation Operative Surgical Procedures Pathologic Pathology Pathway interactions Pattern Pharmaceutical Preparations Pharmacology Phenotype Physiological Public Health Publishing Role Rupture Signal Transduction Smooth Muscle Specificity Specimen System Testing Thinness Thoracic Aortic Aneurysm Tissues Vascular remodeling Vasoconstrictor Agents Work base blood pressure elevation blood pressure reduction cadherin 5 cell growth experimental study high risk insight mechanical load mechanotransduction new therapeutic target novel prevent programs response shear stress therapeutic target tool

项目摘要

Project Summary This project is based on the view that aneurysms represent a pathological response to high wall strain in which the artery wall thins and weakens instead of thickening and strengthening as it does in normal compensatory artery wall remodeling. We hypothesize that inflammatory effects of endothelial cell responses to disturbances in blood flow, and from altered signaling due to extracellular matrix remodeling are important drivers of this switch from compensatory to pathological remodeling. The proposed experiments will test these hypotheses and elucidate mechanisms that link inflammation to aneurysm initiation or progression. We will use two complementary model systems. The first is Marfan syndrome (MFS) mice, which develop severe pathological vascular remodeling and thoracic aortic aneurysms due to a defect in fibrillin 1. The second is continuous infusion of two vasoconstrictors, which induce either compensatory vascular remodeling or moderate pathological remodeling in response to elevated blood pressure. Comparison of these systems will therefore allow us to identify differences between physiological and pathological remodeling of the aorta. Aim 1 will test the effects of mutations in a critical flow-sensing gene that specifically abolish mechanotransduction pathways without compromising overall functions (with Cores B and C). In Aim 2, we will test effects of mutations in integrins and interacting molecules that specifically affect the inflammatory aspects of matrix remodeling (with Cores B and C). In Aim 3, we will investigate the role of flow in regulating expression of Angiotensin II receptor 1, a well- established mediator of aneurysm formation (with Project 1 and Cores B and C). We will also contribute expertise in mechanotransduction to studies in Projects 1, 2 and 4. Results from these experiments will provide an understanding of how specific inflammatory pathways contribute to thoracic aortic aneurysms (TAAs) and thereby identify potential new targets for pharmacological intervention.

项目总结