Role of RhoA in small AAA growth

RhoA 在小 AAA 生长中的作用

• 批准号: 10295147
• 负责人: Zhenheng Guo
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295147
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Address; Adhesions; Age; Aneurysm; Animal Model; Aorta; Biological Assay; Biological Markers; Blood; Blood Vessels; Caliber; Caring; Cell Count; Clinical; Clinical Trials; Clinical assessments; Data; Diagnosis; Disease; Early Diagnosis; Elastin; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Evaluation; Failure; Feasibility Studies; Future; Goals; Growth; Human; In Vitro; Infiltration; Injury; Lead; Leukocytes; Life; Lipopolysaccharides; Matrix Metalloproteinases; Measurement; Measures; Mediating; Medical; Methods; Mus; Natural History; Operative Surgical Procedures; Pathology; Patients; Permeability; Pharmacology; Play; Prevention; Process; Proteins; Research Priority; Risk; Risk Assessment; Risk Factors; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Serum; Smooth Muscle Myocytes; Stains; Sudden Death; Surgeon; Testing; Time; Tissues; Transferase; Vascular Diseases; Veterans; Woman; base; clinical risk; exoenzyme; fasudil; follow-up; human subject; human tissue; imaging study; inhibitor; innovation; large datasets; men; monocyte; mouse model; novel; novel therapeutics; population based; predictive marker; prevent; preventable death; prospective; repaired; rhoA GTP-Binding Protein; screening; translational study; treatment strategy

Project Summary/Abstract An abdominal aortic aneurysm (AAA) is a vascular condition where a major blood vessel in the body can degenerate, balloon in size leading to ultimate rupture and sudden death. Currently, an AAA is identified through imaging studies performed as part of a screening study or incidentally when evaluating for other abdominal pathology. Given that the most important clinical parameter in predicting rupture is the maximal aortic diameter, a normal aorta of 2.0 cm or less requires no further evaluation, whereas a large aorta >5.5 cm in men and >5.0 cm in women requires surgery. Based upon a large VA population based prospective analysis, 20% of veterans with small aortas (3.0-5.4 cm) will grow rapidly and may pose a threat to the life of the veteran. Unfortunately, we do not know which small AAAs will grow rapidly, others slowly, and still others not at all. Failure to identify rapidly growing small AAAs will lead to a certain but preventable death. Thus, there is a critical need to develop predictive markers for rapidly growing small AAAs so that surgery can be performed timely. The medical management of small AAA is one of the top research priorities in the care of the Veterans with vascular disease. We hope to establish our central hypothesis that RhoA mediated monocyte adhesion to the aortic endothelium leads to endothelial barrier injury, subsequent monocyte transmigration, increased aortic wall destruction, and ultimate small AAA growth. This hypothesis will be tested by the following specific aims: 1) To determine whether the activation of RhoA in monocytes from Veteran subjects with a growing small AAA will lead to increased monocyte adhesion, and endothelial barrier injury, 2) To determine whether monocyte RhoA plays a causal role in AAA formation in the animal model, 3) To determine whether high RhoA protein activity isolated in the monocytes from Veteran subjects with small AAA will predict the growth of the small AAA (>0.1 cm/year). Current studies have shown the possibility of RhoA as a biomarker for disease in both AAA formation and growth. RhoA and monocyte activity were identified to be highly expressed in both the serum and aortic tissue from subjects with AAA compared to age-matched controls, The role of RhoA in comparing human subjects with growing AAA or stable AAA has yet to be elucidated. To date, there is a lack of translatability of the data obtained from tissue in human subjects (late in the disease process) or findings from animal models to the human patient with small AAAs. The innovation of this project is the connection between the use of RhoA and monocyte activity into an overarching mechanism of biomarkers, leading to future novel therapies to control small AAA growth. This is a translational study using human Veteran subjects with the readily available 1,169 veterans identified with small AAAs (3.0-5.4 cm) collected over a 10-year period to make the completion of the proposed study feasible. Ultimately, we hope that the data collected will open the possibility of identifying approaches to both predicting and limiting small AAA growth.

项目总结/文摘