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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：
10368129
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368129
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.

项目总结/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、静脉移植物疾病和心脏移植物动脉病，是病理性血管平滑肌细胞（VSMC）激活。 VSMC活化导致新生内膜形成和损伤血管的再闭塞。战略防止异常的VSMC重塑，例如药物洗脱支架中使用的细胞生长抑制剂，具有不希望的损害再内皮化的作用。这种内皮愈合的衰减增加了血管内皮细胞损伤的风险。新动脉粥样硬化和晚期支架血栓形成。为了防止病理性VSMC生长，但不重新- 因此，迫切需要鉴定可以被试剂靶向的细胞表面蛋白，区分VSMC和内皮细胞（EC）并调节VSMC利用的细胞过程在病理性重塑过程中不影响内皮愈合。本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，以定义1）确定细胞表面蛋白和VSMC靶向适体调节VSMC的作用机制而不是EC过程;和2）确定这些细胞和过程特异性配体对新生内膜的影响，形成和再内皮化后急性血管损伤。我们最近发现了一种VSMC特异性抗- 迁移适体可阻止VSMC迁移，但对EC迁移无影响。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-β无影响。介导的VSMC增殖。这些数据提示了PDGFR-β迁移和增殖的新概念，可以分离信令。我们现在已经鉴定了另外两种靶向VSMC的适体， VSMC，而不是EC，通过起源于细胞表面的未知机制增殖和凋亡。我们将检验VSMC细胞表面蛋白和信号通路对于VSMC细胞增殖和分化所必需的整体假设。急性血管损伤后的迁移、增殖和凋亡可能是细胞特异性调节的，防止新生内膜形成而不改变EC再内皮化。在目标1中，我们将定义机制 VSMC PDGFR-β依赖性迁移与PDGFR-β依赖性增殖分离，可被抑制以防止新生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文库的新应用，并定义机制其中VSMC增殖可以在VSMC中被特异性抑制，以防止新生内膜形成，影响再内皮化。目的3：探讨VSMC在细胞增殖过程中的作用机制及细胞表面蛋白可以诱导细胞凋亡以限制新生内膜形成，同时保持再内皮化。完成本研究将有助于了解调控VSMC迁移、增殖和凋亡的机制防止新生内膜形成和保持再内皮化，适用于许多急性血管疾病