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

• 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
• 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

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.

大约有9200万美国成年人至少患有一种心血管疾病（CVD）， 心血管疾病和中风的直接医疗费用估计超过3150亿美元。在美国退伍军人中，CVD是 导致住院的主要原因和残疾的主要原因， 研究和开发，约80%的退伍军人目前有两个以上的心血管疾病危险因素。粥样硬化 疾病是CVD的主要形式。其严重程度和相关发病率/死亡率为 这不仅取决于总的斑块负荷，还取决于斑块的稳定性或易损性。因此 更好地了解参与生长和稳定的潜在机制和细胞类型， 斑块对于提供新的疗法至关重要。ADP核糖基化因子6（Arf 6）是RAS家族的成员， 调节细胞增殖和运动以及膜运输的小GTP酶。Arf 6参与了 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， 内皮细胞渗透性和血管生成。然而，Arf 6在动脉粥样硬化中的作用尚未被证实。 介绍了我们的目的是阐明调节全身和组织特异性Arf 6对斑块的影响， 负荷、组成和稳定性，以及探索作为抗动脉粥样硬化药物的药理学Arf 6抑制 疗法