Vascular smooth muscle cell apoptosis in intimal hyperplasia

内膜增生中血管平滑肌细胞凋亡

基本信息

批准号：
9110305
负责人：
Bo Liu
金额：
$ 37.83万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9110305
关键词：
Acceleration Affect Angioplasty Apoptosis Apoptosis Regulation Gene Apoptotic Arteries Attenuated Automobile Driving Blood Circulation Blood Vessels Bone Marrow Bypass CCL2 gene Carotid Arteries Cell Death Cell Nucleus Cells Clinical Data Endothelial Cells Endothelium Fibroblasts Gene Transfer Growth Health Human Hyperplasia In Vitro Induction of Apoptosis Injury Interleukin-8B Receptor Intervention Knowledge Medial Mediating Modeling Modification Molecular Mutation Myofibroblast Natural regeneration Operative Surgical Procedures Oxidative Stress PPBP gene Paracrine Communication Patients Peptides Peripheral Phenotype Phosphorylation Production Property Rattus Recruitment Activity Regulation Reporting Research Role Series Signal Pathway Signal Transduction Smooth Muscle Myocytes Stimulus Testing Therapeutic Intervention Translating Transplantation Tunica Adventitia UV Radiation Exposure Vascular Smooth Muscle adenoviral-mediated base cell type chemokine cytokine design diphtheria toxin receptor expectation improved in vivo injured innovation migration neutralizing antibody new therapeutic target novel overexpression paracrine prevent progenitor promoter protein kinase C-delta repaired response to injury restenosis therapeutic development tool vascular bed

项目摘要

DESCRIPTION (provided by applicant): Intimal hyperplasia is a major cause of restenosis that occurs at an unacceptably high rate, particularly in peripheral vascular beds. Based on our findings made in a rat carotid injury model, we put forward an unconventional hypothesis that apoptosis of vascular smooth muscle cells (SMCs) induced by primary vascular intervention influences the entire vessel wall including intimal endothelial cells as well as cells of the arteral adventitia. Our data suggest that SMCs signal to the adventitia and endothelium through protein kinase C-delta (PKCd)-dependent production of chemokines. We have identified MCP-1 as a critical paracrine factor through which SMCs modulate adventitial fibroblasts. By combining PKCd gene transfer with an MCP-1 neutralizing antibody, we blocked fibroblasts from migrating into the intima and doubled the inhibitory effect of PKCd on IH. However, the mechanism underlying acceleration of re-endothelialization remains unclear. In Specific Aim I, we plan to test the hypothesis that apoptotic SMCs stimulate re- endothelialization by driving recruitment of bone marrow-derived cells which in turn contribute to endothelial regeneration through differentiation or paracrine effects. We will also test whether CXCL7 underlies the recruitment of pro-endothelial cells. In Specific Aim II, we will test whether the paracrine effects produced by PKCd-expressing SMCs are general properties of apoptotic cells. In vitro, we will examine whether induction of apoptosis with physiologically relevant stimuli such as oxidative stress and cytokines produce paracrine factors that attract adventitial fibroblasts or bone marrow-derived circulating proangiogenic cells. In vivo, we will drive arterial smooth muscle cells to apoptosis b expressing human diphtheria toxin receptor with an expectation that enhanced apoptosis will reduce SMC accumulation, stimulate migration of adventitial fibroblasts but accelerate re-endothelialization. In Specific Aim III, we will attempt to translate the PKCd modifications we developed in preliminary studies to attenuate intimal hyperplasia by stimulating apoptosis and re- endothelialization but suppressing influx of adventitial fibroblasts. In summary, this is a significant and highly translational project that is likely to expand our knowledge on cell death and therapeutic development.

描述（由申请人提供）：内膜增生是再狭窄发生率高得令人无法接受的主要原因，特别是在外周血管床中。根据我们在大鼠颈动脉损伤模型中的发现，我们提出了一个非常规的假设，即细胞凋亡。原发性血管介入诱导的血管平滑肌细胞（SMC）影响整个血管壁，包括内膜内皮细胞以及动脉外膜细胞。 SMC 通过蛋白激酶 C-δ (PKCd) 依赖性产生趋化因子向外膜和内皮发出信号。我们通过将 PKCd 基因转移与 MCP-1 相结合，将 MCP-1 确定为 SMC 调节外膜成纤维细胞的关键旁分泌因子。中和抗体，我们阻止成纤维细胞迁移到内膜并使 PKCd 对 IH 的抑制作用加倍，然而，加速 IH 的机制却是这样的。在具体目标 I 中，我们计划测试这样的假设：凋亡的 SMC 通过驱动骨髓来源的细胞募集来刺激再内皮化，而骨髓来源的细胞反过来又通过分化或旁分泌作用促进内皮再生。 CXCL7 是否是促内皮细胞募集的基础在特定目标 II 中，我们将测试表达 PKCd 的 SMC 产生的旁分泌效应是否是一般特性。在体外，我们将检查生理相关刺激（例如氧化应激和细胞因子）是否会产生吸引外膜成纤维细胞或骨髓来源的循环促血管生成细胞的细胞凋亡。在体内，我们将驱动动脉平滑肌细胞。细胞凋亡 b 表达人白喉毒素受体，预期增强的细胞凋亡将减少 SMC 积累，刺激外膜成纤维细胞迁移，但具体加速再内皮化。目标 III，我们将尝试转化我们在初步研究中开发的 PKCd 修饰，通过刺激细胞凋亡和再内皮化但抑制外膜成纤维细胞的流入来减轻内膜增生。总之，这是一个重要且高度转化的项目，可能会扩大。我们在细胞死亡和治疗开发方面的知识。