Profilin-1's Role in Atherosclerosis

Profilin-1 在动脉粥样硬化中的作用

• 批准号: 10313442
• 负责人: Abigail Elizabeth Allen Gondringer
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313442
• 关键词: Profilin; Role; Atherosclerosis

PROJECT SUMMARY Atherosclerosis is a major cause of cardiovascular-related death worldwide. Actin-binding protein Profilin-1 (Pfn1), an important regulator of actin cytoskeleton is overexpressed in atherosclerotic plaques in preclinical models as well as in human disease. Global reduction of Pfn1 by embryonic heterozygous knockout (KO) of the Pfn1 gene in mice displays diminished vascular infiltration of pro-atherogenic inflammatory cells (i.e. macrophages) and plaque size in experimentally induced atherosclerosis, suggesting that Pfn1 diminution confers partial protection against atherosclerosis. Since atherosclerosis is a disease that involves pathology of multiple cell types (vascular endothelial cells (VEC), various types of immune cells, smooth muscle cells), previous studies could not discern Pfn1’s contribution from specific cell types in atherosclerosis progression. Furthermore, lack of marketed small molecule inhibitors of Pfn1 has hampered translational efforts of targeting Pfn1 as a potential strategy to mitigate atherosclerosis development and/or progression. The goal of the proposed study is to specifically dissect the role of endothelial Pfn1 in atherosclerosis and further explore whether Pfn1 is an impactful pharmacological target to diminish atherosclerosis. To address this goal, a novel inducible VEC-specific Pfn1 KO mouse model and novel small molecule investigative compounds targeting the Pfn1-actin interaction interface will be used. Angiogenesis and vascular permeability facilitate nutrient delivery and leukocyte invasion, promoting atherogenesis, plaque growth and eventually plaque rupture. We have shown that endothelial Pfn1 is an important mediator of angiogenesis in physiological settings. We also found that Pfn1 depletion in VEC improves barrier function, a finding consistent with Pfn1’s ability to exacerbate agonist-induced microvascular hyper-permeability in vivo. Thus, we hypothesize that inhibition of vascular endothelial Pfn1 function exerts an atheroprotective effect by reducing plaque angiogenesis and vascular permeability. Aim 1A will utilize a novel EC-specific Pfn1 KO mouse to study atherosclerosis progression in Pfn1 deficient mice. In Aim 1B, in vitro endothelial perturbation of Pfn1 expression will be used to reveal the effect of Pfn1 to changes in leukocytic adhesion and extravasation in static and flow-based assays, as well as changes in endothelial contractility. Aim 2 will winnow available novel Pfn1:actin interaction inhibitors to the most effective inhibitor as determined by endothelial proliferation, migration, biochemical assays, and in vivo angiogenesis assays. The optimal inhibitor will be used in ApoE deficient mouse model as a potential therapeutic for atherosclerosis.

项目摘要 动脉粥样硬化是全球心血管相关死亡的主要原因。 （PFN1），肌动蛋白细胞骨架的重要常规者在临床前的开胃斑块中过表达 模型以及人类疾病。 小鼠II中小鼠中的PFN1基因显示出促动脉粥样硬化细胞的血管浸润减少（即 巨噬细胞）和实验诱导的动脉粥样硬化中的斑块大小，建议PFN1二聚体 赋予动脉粥样硬化的部分保护。 多种CELLE类型（血管内皮细胞（VEC），各种类型的免疫细胞，平滑肌细胞）， 前研究无法辨别PFN1在动脉粥样硬化进展中特定细胞类型的贡献。 此外，缺乏销售的小分子PFN1诱因阻碍了靶向的转化 PFN1是减轻动脉粥样硬化发展和/或进展的潜在策略。 支撑研究是要专门展示触及PFN1在动脉粥样硬化中的作用，并进一步探索是否是否探索是否是否 PFN1是一种有影响力的药物，可以解决这个目标，这是一种新颖的诱导性 VEC特异性PFN1 KO Mousel和NOLECULE调查化合物靶向Pfn1-肌动蛋白 相互作用界面将被使用。 白细胞发明，促进动脉粥样硬化，斑块生长和最终的斑块破裂。 内皮PFN1是生理环境中血管生成的重要介体。 VEC中的抑郁改善了障碍功能，这一发现与PFN1加剧激动剂的能力一致 体内微血管高渗透性。 功能通过减少斑块血管生成和血管渗透性发挥动力保护作用。 AIM 1A将利用新型的EC特异性PFN1 KO小鼠研究PFN1 Deficien1中的动脉粥样硬化1 小鼠在AIM 1B中，PFN1 Express的体外进行式式序列序列 静态和基于流的测定中白细胞粘附和渗出的变化 内皮收缩能力2。 抑制剂是由其他人的殖民地，迁移，生化测定和体内角质症决定的抑制剂 测定法。 动脉粥样硬化。