Role of RhoA in small AAA growth

RhoA 在小 AAA 生长中的作用

• 批准号: 10683701
• 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/10683701
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Adhesions; Age; Aneurysm; Animal Model; Aorta; Biological Assay; Biological Markers; Blood; Blood Vessels; Caring; Cell Count; Clinical; Clinical Trials; Clinical assessments; Data; Diagnosis; Diameter; Disease; Early Diagnosis; Elastin; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Evaluation; Failure; Feasibility Studies; Future; Goals; Growth; Human; In Vitro; Infiltration; Injury; Leukocytes; Life; Lipopolysaccharides; Matrix Metalloproteinases; Measurement; Measures; Mediating; Medical; Methods; Mus; Natural History; Operative Surgical Procedures; Pathology; Patients; Permeability; 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; Tissues; Transferase; Vascular Diseases; Veterans; Woman; clinical risk; exoenzyme; fasudil; follow-up; human subject; human tissue; imaging study; inhibitor; innovation; large datasets; men; migration; monocyte; mouse model; novel; novel therapeutics; pharmacologic; 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/摘要 腹主动脉瘤（AAA）是一种血管疾病，其中体内的主要血管可以 退化，气球大小导致最终破裂和突然死亡。目前，AAA通过以下方式识别： 作为筛选研究的一部分或在评价其他腹部疾病时偶然进行的影像学检查 病理鉴于预测破裂的最重要临床参数是最大主动脉直径， 2.0 cm或更小的正常主动脉不需要进一步评估，而男性大主动脉>5.5 cm， 女性中的cm需要手术。根据一项基于退伍军人事务部人群的前瞻性分析，20%的退伍军人 而小胸突（3.0-5.4厘米）则会迅速生长，并可能对退伍军人的生命构成威胁。不幸的是， 我们不知道哪些小型AAA会快速增长，其他的会缓慢增长，还有一些则根本不会增长。未能识别 快速增长的小AAA将导致一定但可预防的死亡。因此，迫切需要发展 快速生长的小AAA的预测标志物，以便及时进行手术。 小型AAA的医疗管理是退伍军人护理的首要研究重点之一， 血管疾病我们希望建立我们的中心假设，即RhoA介导单核细胞粘附到 主动脉内皮导致内皮屏障损伤，随后单核细胞迁移，主动脉壁增加 毁灭和最终的小AAA级增长。这一假设将通过以下具体目标进行检验：1） 确定来自患有生长中的小AAA的退伍军人受试者的单核细胞中RhoA的活化是否 将导致单核细胞粘附增加和内皮屏障损伤，2）为了确定是否 单核细胞RhoA在动物模型中AAA形成中起因果作用，3）为了确定高RhoA是否 从患有小AAA的退伍军人受试者的单核细胞中分离的RhoA蛋白活性将预测 小AAA的生长（>0.1 cm/年）。目前的研究表明RhoA作为生物标志物的可能性 在AAA的形成和生长方面的疾病。RhoA和单核细胞活性被鉴定为高表达 与年龄匹配的对照组相比，在AAA受试者的血清和主动脉组织中，RhoA的作用 将患有生长型AAA或稳定型AAA的人类受试者进行比较尚未阐明。到目前为止，缺乏 从人类受试者的组织中获得的数据的可翻译性（在疾病过程的后期）或 将动物模型应用于患有小AAA的人类患者。这个项目的创新之处在于 RhoA和单核细胞活性的使用成为生物标志物的总体机制，导致未来新的 治疗以控制小AAA生长。这是一项使用人类退伍军人受试者的转化研究， 可用的1，169名退伍军人确定与小AAA（3.0-5.4厘米）收集超过10年的时间，使 完成拟议的研究是可行的。最终，我们希望收集的数据将开启以下可能性： 确定预测和限制AAA小规模增长的方法。