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Deciphering mechanisms of vascular disease with cell and process specific ligands

用细胞和过程特异性配体破译血管疾病的机制

基本信息

批准号：
10116449
负责人：
William H Thiel
金额：
$ 38.13万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116449
关键词：
Acute Address Agonist Apoptosis Apoptotic Arterial Disorder Arterial Injury Binding Biological Assay Blood Vessels Blood flow Bypass CRISPR library Cell Proliferation Cell Surface Proteins Cell physiology Cell surface Cells Cessation of life Data Disease Endothelial Cells Endothelium Event Fluorescence Goals Growth Inhibitors Impairment In Vitro Injury Ligands Mediating Occlusion injury Operative Surgical Procedures Oranges PDGFRB gene Pathologic Pharmaceutical Preparations Phenotype Platelet-Derived Growth Factor Platelet-Derived Growth Factor beta Receptor Procedures Process Proliferating Reporting Risk Safety Signal Pathway Signal Transduction Smooth Muscle Myocytes Specificity Stents Testing Tissues Vascular Diseases Vascular Smooth Muscle Vein graft Work aptamer attenuation base cell dedifferentiation cell growth cell motility cell type common treatment drug efficacy efficacious treatment healing heart allograft improved in vivo in vivo Model innovation migration novel platelet-derived growth factor BB preservation prevent public health relevance response restenosis stent thrombosis targeted agent targeted treatment tool vascular abnormality vascular injury vascular smooth muscle cell migration vascular smooth muscle cell proliferation whole genome

项目摘要

Project Summary / Abstract The primary mechanism responsible for many acute vascular disorders, including in-stent restenosis, vein graft disease, and cardiac allograft arteriopathy, is pathological vascular smooth muscle cell (VSMC) activation. VSMC activation leads to neointimal formation and re-occlusion of injured blood vessels. Strategies to prevent abnormal VSMC remodeling, such as cell growth inhibitors used in drug eluting stents, have the undesired effect of impairing re-endothelialization. This attenuation of endothelial healing increases the risk of neoatherosclerosis and late stent thrombosis. In order to prevent pathological VSMC growth, but not re- endothelialization, there is a critical need to identify cell-surface proteins that may can be targeted by agents to distinguish between VSMCs and endothelial cells (ECs) and modulate cellular processes utilized by VSMCs during pathological remodeling that do not affect endothelium healing. The objective of this proposal is to utilize VSMC-targeting aptamers that specifically modulate VSMC migration, proliferation and apoptosis to define 1) define the cell-surface proteins and mechanism of action by which VSMC-targeting aptamers modulate VSMC but not EC processes; and 2) determine the impact of these cell- and process-specific ligands on neointimal formation and re-endothelialization following acute vascular injury. We recently identified a VSMC-specific anti- migratory aptamer that prevents VSMC migration with no effect on EC migration. We determined that the VSMC anti-migratory aptamer operates by antagonizing PDGFR-β activation, but has no effect on PDGF-BB- mediated VSMC proliferation. These data suggest the novel concept that PDGFR-β migration and proliferation signaling may be dissociated. We have now identified two additional VSMC-targeting aptamers that modulate VSMC, but not EC, proliferation and apoptosis through unknown mechanisms originating at the cell surface. We will test the overall hypothesis that VSMC cell surface proteins and signaling pathways necessary for migration, proliferation and apoptosis following acute vascular injury may be cell-specifically modulated to prevent neointimal formation without altering EC re-endothelialization. In Aim 1, we will define the mechanism by which VSMC PDGFR-β dependent migration is dissociated from PDGFR-β dependent proliferation and may be inhibited to prevent neointimal formation without interfering with re-endothelialization. Aim 2 will identify the cell-surface protein, using a novel application of a whole-genome CRISPR library, and define the mechanisms where VSMC proliferation may be specifically inhibited in VSMCs to prevent neointimal formation without impacting re-endothelialization. Aim 3 will determine the mechanism and cell surface-proteins by which VSMC apoptosis may be induced to limit neointimal formation while preserving re-endothelialization. Completion of this study will result in a mechanistic understanding of modulating VSMC migration, proliferation and apoptosis towards preventing neointimal formation and preserving re-endothelialization, with applicability to a number of acute vascular diseases.

项目概要/摘要导致许多急性血管疾病的主要机制，包括支架内再狭窄、静脉移植该病和同种异体移植心脏动脉病一样，都是病理性血管平滑肌细胞（VSMC）激活。 VSMC 激活导致新内膜形成和受损血管的重新闭塞。预防策略异常的 VSMC 重塑，例如药物洗脱支架中使用的细胞生长抑制剂，会产生不良后果损害再内皮化的作用。内皮愈合的减弱会增加以下风险：新生动脉粥样硬化和晚期支架内血栓形成。为了防止病理性 VSMC 生长，但不重新内皮化过程中，迫切需要鉴定可以被药物靶向的细胞表面蛋白区分 VSMC 和内皮细胞 (EC) 并调节 VSMC 使用的细胞过程在不影响内皮愈合的病理重塑过程中。该提案的目的是利用特异性调节 VSMC 迁移、增殖和凋亡的 VSMC 靶向适体定义 1) 定义细胞表面蛋白以及 VSMC 靶向适体调节 VSMC 的作用机制但不是 EC 流程； 2) 确定这些细胞和过程特异性配体对新内膜的影响急性血管损伤后的形成和再内皮化。我们最近发现了一种 VSMC 特异性抗迁移适体可阻止 VSMC 迁移，但不影响 EC 迁移。我们确定 VSMC抗迁移适体通过拮抗PDGFR-β激活起作用，但对PDGF-BB-没有影响介导 VSMC 增殖。这些数据提出了 PDGFR-β 迁移和增殖的新概念信号传导可能会被分离。我们现在已经确定了另外两个 VSMC 靶向适体，可以调节 VSMC（而非 EC）通过源自细胞表面的未知机制进行增殖和凋亡。我们将检验以下总体假设：VSMC 细胞表面蛋白和信号通路是急性血管损伤后的迁移、增殖和凋亡可能受到细胞特异性调节防止新内膜形成而不改变 EC 再内皮化。在目标 1 中，我们将定义机制通过这种方式，VSMC PDGFR-β 依赖性迁移与 PDGFR-β 依赖性增殖分离，并且可能被抑制以防止新内膜形成而不干扰再内皮化。目标 2 将确定细胞表面蛋白，使用全基因组 CRISPR 库的新应用，并定义其机制其中 VSMC 增殖可能被特异性抑制，以防止新内膜形成，而无需影响再内皮化。目标 3 将确定 VSMC 的机制和细胞表面蛋白可以诱导细胞凋亡以限制新内膜形成，同时保留再内皮化。完成这项研究将带来调节 VSMC 迁移、增殖和凋亡的机制理解旨在防止新内膜形成和保留再内皮化，适用于许多急性血管疾病。