Role of ARF6 in atherosclerotic burden and severity

ARF6 在动脉粥样硬化负荷和严重程度中的作用

基本信息

批准号：
10044413
负责人：
Lisa A Lesniewski
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044413
关键词：
ADP-ribosylation factor 6 Adult Apolipoprotein E Area Arterial Fatty Streak Atherogenic Diet Atherosclerosis Body Temperature Cardiovascular Diseases Carotid Arteries Cell Adhesion Cell Proliferation Cells Clinical Data Deposition Development Disease Endothelial Cells Endothelium Euthanasia Event Family Gel Growth Guanosine Triphosphate Phosphohydrolases Health Care Costs Health Services Research Healthcare Systems Heterozygote Histologic Hospitalization Human Hydrogels Immune Incidence Inflammation Inflammatory Lesion Ligation Lipids Liquid substance LoxP-flanked allele Matrix Metalloproteinases Measures Membrane Methods Monomeric GTP-Binding Proteins Morbidity - disease rate Mus Myocardial Infarction Necrosis Operative Surgical Procedures Permeability Pharmacology Phenotype Plant Roots Plasma Play Polymers Proteins Recombinants Risk Factors Role Rupture Severities Silk Site Smooth Muscle Stroke T-Lymphocyte Temperature Time Tissues Veterans angiogenesis cardiovascular disorder risk cell motility cell type disability endothelial dysfunction improved in vivo inhibitor/antagonist innovation macrophage member mortality novel novel therapeutics prevent research and development small molecule small molecule inhibitor trafficking

项目摘要

Approximately 92 million US adults have at least one form of cardiovascular disease (CVD), with the annual direct health care cost of CVD and stroke estimated to exceed $315 billion. Among US Veteran’s, CVD is the leading cause of hospitalizations and a major cause of disability and according to the VA Health Services Research and Development, ~80% of Veteran’s present with more than two CVD risk factors. Atherosclerotic diseases are a predominate form of CVD. The severity and associated morbidity/mortality of which is determined not only by overall plaque burden, but also by the stability, or vulnerability, of plaques. Thus, a better understanding of the underlying mechanisms and cell types involved in the growth and stability of plaques is critical to inform novel therapies. ADP ribosylation factor 6 (Arf6) is a member of the RAS family of small GTPases that regulates cell proliferation and motility as well as membrane trafficking. Arf6 is involved in inflammatory and arterial functions related to atherosclerosis, including immune cell adhesion/activation, endothelial cell permeability and angiogenesis. However, a role for Arf6 in atherosclerosis has not been described. We aim to elucidate the effects of modulating whole body and tissue-specific Arf6 on plaque burden, composition and stability, as well as explore pharmacological Arf6 inhibition as an anti-atherosclerotic therapy.

大约 9200 万美国成年人患有至少一种形式的心血管疾病 (CVD)，每年在美国退伍军人中，CVD 和中风的直接医疗费用估计超过 3150 亿美元。根据退伍军人管理局健康服务中心的说法，这是导致住院的主要原因和残疾的主要原因研究与开发，约 80% 的退伍军人存在两种以上的动脉粥样硬化危险因素。疾病是 CVD 的主要形式，其严重程度和相关发病率/死亡率是不仅取决于斑块的总体负荷，还取决于斑块的稳定性或脆弱性。更好地了解参与生长和稳定性的潜在机制和细胞类型 ADP 核糖基化因子 6 (Arf6) 是 RAS 家族的成员，对于新疗法至关重要。调节细胞增殖和运动以及膜运输的小 GTP 酶。与动脉粥样硬化相关的炎症和动脉功能，包括免疫细胞粘附/激活，然而，Arf6 在动脉粥样硬化中的作用尚未得到证实。我们的目标是阐明调节全身和组织特异性 Arf6 对斑块的影响。负荷、成分和稳定性，并探索 Arf6 抑制作为抗动脉粥样硬化药物的药理作用治疗。