Specific Beta-tubulin Isotype Involvement in Foam Cell Formation and Progression of Atherosclerosis

特定 β-微管蛋白同种型参与泡沫细胞形成和动脉粥样硬化进展

• 批准号: 9925793
• 负责人: Veronica E Contreras-Shannon
• 金额: $ 13.5万
• 依托单位: ST. MARY'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-09 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925793
• 关键词: Abnormal Cell; Address; Aneurysm; Animal Model; Antibodies; Aortic Diseases; Arterial Fatty Streak; Atherosclerosis; Behavior; Binding; Biological; Blood Vessels; Bone Marrow; Cause of Death; Cell Line; Cell Shape; Cell Size; Cell physiology; Cells; Cellular Morphology; Cerebrovascular Disorders; Cessation of life; Colchicine; Cytoskeleton; Data; Deposition; Development; Disease; Drug Targeting; Effector Cell; Event; Foam Cells; Gene Expression; Health; In Vitro; Individual; Inflammation; Ingestion; Knowledge; Lead; Lesion; Lipids; Measures; Messenger RNA; Methods; Microtubules; Morbidity - disease rate; Morphology; Mus; Myocardial Infarction; Myocardial Ischemia; Nocodazole; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Play; Polymers; Prevention; Property; Protein Secretion; Proteins; Quantitative Reverse Transcriptase PCR; Role; Stroke; Structure; Tissues; Tubular formation; alpha Tubulin; base; beta Tubulin; cell motility; cellular targeting; design; differential expression; dimer; human model; in vivo; innovation; macrophage; monocyte; mortality; mouse model; novel; oxidized lipid; polymerization; prevent; repaired

Project Summary/Abstract Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality worldwide. Current treatments for atherosclerosis focus on prevention or vessel repair with very few targeting the cellular events leading to the progression of atherosclerosis. At the cellular level, the main effector cell of atherosclerosis is the foam cell which is formed when macrophages undergo a morphological change associated with engulfment of lipids. This is facilitated by the cytoskeleton which plays important roles in cell shape and function. Important components of the cytoskeleton are the tubular polymers formed by the polymerization of dimers of α- and β- tubulin called microtubules. The stability, dynamic properties, and behavior of a microtubule depend on the composition of β-tubulin isotypes, of which there are many. The expression of these individual β-tubulin isotypes can differ greatly across cell or tissue type. We hypothesize that a specific subset of β-tubulin isotypes regulates foam cell formation and function. To understand the role of β-tubulin isotypes in foam cell formation and function, we propose a comprehensive approach integrating in vitro and animal models to gain an understanding of the biologically relevant roles β-tubulin isotypes play in foam cell formation and the development of atherosclerotic plaques. We aim to establish the expression, distribution, and role of individual β-tubulins during foam cell formation in vitro using primary cells (bone-marrow derived macrophage) and to determine the mechanism of β- tubulin-dependent foam cell formation in vivo using mouse models of atherosclerosis. β-tubulin isotype levels and cellular distribution will be measured in primary cells undergoing foam cell formation and within aortic lesions using β-tubulin isotype-specific antibodies. β-tubulin gene expression will be quantified in cells and aortic tissue using qRT-PCR. In addition, the effect that altering individual β-tubulin isotypes in primary cells or, with β-tubulin binding drugs in mice, has on foam cells will be assessed. The proposed study will define the specific β-tubulin isotypes involved in foam cell formation. Knowledge that we will gain could be used to design specific drugs that inhibit foam cell formation, and subsequent plaque formation, by targeting specific β-tubulin isotypes.

项目概要/摘要 动脉粥样硬化性心血管疾病是全世界发病和死亡的主要原因。当前的 动脉粥样硬化的治疗侧重于预防或血管修复，很少针对细胞事件 导致动脉粥样硬化的进展。在细胞水平上，动脉粥样硬化的主要效应细胞是 当巨噬细胞经历与吞噬相关的形态变化时形成的泡沫细胞 脂质。细胞骨架促进了这一点，细胞骨架在细胞形状和功能中发挥着重要作用。重要的 细胞骨架的组成部分是由α-和β-二聚体聚合形成的管状聚合物 微管蛋白称为微管。微管的稳定性、动态特性和行为取决于 β-微管蛋白同种型的组成，其中有很多种。这些单独的 β-微管蛋白同种型的表达 不同细胞或组织类型之间可能存在很大差异。我们假设 β-微管蛋白同种型的特定子集调节 泡沫细胞的形成和功能。为了了解 β-微管蛋白同种型在泡沫细胞形成和功能中的作用， 我们提出了一种整合体外和动物模型的综合方法，以了解 β-微管蛋白同种型在泡沫细胞形成和动脉粥样硬化发展中发挥的生物学相关作用 牌匾。我们的目标是确定单个 β-微管蛋白在泡沫细胞过程中的表达、分布和作用 使用原代细胞（骨髓来源的巨噬细胞）在体外形成并确定 β- 的机制 使用动脉粥样硬化小鼠模型体内微管蛋白依赖性泡沫细胞形成。 β-微管蛋白同种型水平 将测量正在形成泡沫细胞的原代细胞和主动脉病变内的细胞分布 使用 β-微管蛋白同种型特异性抗体。细胞和主动脉组织中的β-微管蛋白基因表达将被量化 使用 qRT-PCR。此外，改变原代细胞中单个 β-微管蛋白同种型或使用 β-微管蛋白的效果 在小鼠中结合药物，已对泡沫细胞进行了评估。拟议的研究将定义特定的 β-微管蛋白 参与泡沫细胞形成的同种型。我们将获得的知识可用于设计特定药物 通过针对特定的 β-微管蛋白同种型来抑制泡沫细胞形成以及随后的斑块形成。