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Mechanisms and Significance of Angiogenesis in AAA Disease

AAA 疾病中血管生成的机制和意义

基本信息

批准号：
8403798
负责人：
RONALD L DALMAN
金额：
$ 22.54万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403798
关键词：
Abdominal Aortic Aneurysm Adenoviruses Adult American Aneurysm Angiogenesis Inhibitors Angiotensin II Aorta Aortic Aneurysm BAY 54-9085 Biological Assay Blood Vessels Caliber Cell Density Cells Cessation of life Chronic Clinical Collagen Data Development Disease Disease Progression Elastases Elastin Enzyme-Linked Immunosorbent Assay Enzymes Experimental Models Extracellular Domain Extracellular Matrix FDA approved Failure Family suidae Functional disorder Future Genetic Genetic Recombination Growth Factor Health Histologic Human Human Characteristics Image Imaging Techniques In Situ Infiltration Inflammation Inflammatory Infusion procedures Intervention Kinetics Knockout Mice Laboratories Learning Leukocytes Literature Macrophage Activation Medial Mediating Mediator of activation protein Medical Methods Modeling Monitor Morbidity - disease rate Mus Operative Surgical Procedures Pancreatic Elastase Pathogenesis Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Plasma Process Production Proteolysis Receptor Protein-Tyrosine Kinases Risk Rodent Model Role Rupture Signal Transduction Smooth Muscle Myocytes Specimen Staining method Stains Sudden Death Surgical Management System Testing Therapeutic Translating Translations Tunica Adventitia Tyrosine Kinase Receptor Inhibition Ultrasonography VEGFR inhibition Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Virus abdominal aorta abstracting angiogenesis antiangiogenesis therapy attenuation base clinically relevant efficacy testing extracellular factor A improved inhibitor/antagonist macrophage male monocyte novel premature prevent repaired research study tool translational study treatment strategy

项目摘要

Project Summary/Abstract Abdominal aorta aneurysm (AAA) is a common and lethal disease of adult Americans. Progressive AAA enlargement, over the course of months to years, leads to ever-increasing risk of sudden death from catastrophic rupture. Currently, rupture can only be prevented by timely surgical repair, which carries considerable morbidity and/or requirements for ongoing surveillance and periodic re-intervention. Prior attempts to identify specific mediator or pathway targets for medical intervention have not translated to effective clinical therapies. Although medial and adventitial neovessel formation (mural angiogenesis) is well recognized in human and experimental AAA, the role of angiogenesis in AAA pathogenesis has not been studied. Based on our preliminary findings that VEGF-A-producing cells were increased in aneurysmal aortae, and that inhibition of VEGF signaling by either soluble VEGFR-2 or VEGFR inhibitor sunitinib significantly suppressed AAA progression, it is our fundamental hypothesis that VEGF-A-mediated mural angiogenesis is a critical and rate-limiting factor in aortic aneurysm pathogenesis, and that manipulation of VEGF signaling will modulate progression and regression of experimental aneurysms. To pursue this hypothesis, we propose the following Specific Aims: 1. Determine cellular origin and magnitude of aortic VEGF-A production in AAA disease. 2. Define the role of VEGF-A signaling in AAA disease progression. 3. Evaluate ability of FDA-approved VEGFR inhibitors to stabilize or regress AAA. Using the well-established mouse aortic elastase infusion model of human AAA disease, we will employ immunostaining, confocal imaging and ELISA assays to analyze the kinetics and cellular origins of VEGF-A expression during aneurysm development. We will use multiple genetic tools to block VEGF-A both in a systemic and cell-specific manner to define the role of VEGF-A-driven angiogenesis in AAA pathogenesis. We will further evaluate the effects of FDA-approved anti-angiogenesis drugs (sunitinib and sorafenib) on the progression and regression of AAA. Confirming the pathogenetic significance of VEGF-A-driven angiogenesis in AAA disease will facilitate the rapid translation of emerging anti-angiogenesis therapeutic strategies to effective non-surgical methods of aneurysm suppression.

项目总结/文摘