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（由适用提供）：内膜增生是再狭窄的主要原因，其发生率很高，尤其是在外围血管床中。根据我们在大鼠颈动脉损伤模型中提出的发现，我们提出了一个非常规的假设，即原发性血管干预诱导的血管平滑肌细胞（SMC）凋亡会影响整个容器壁，其中包括内膜内皮细胞以及动脉质激增的细胞。我们的数据表明，SMC通过蛋白激酶C-DELTA（PKCD）依赖性趋化因子的蛋白激酶C-DELTA（PKCD）向内皮发出信号。我们已经将MCP-1确定为SMCS调节外部成纤维细胞的关键旁分泌因子。通过将PKCD基因转移与MCP-1中和抗体相结合，我们阻止了成纤维细胞迁移到内膜中，并使PKCD对IH的抑制作用增加了一倍。然而，重新皮层化加速度的基础机制尚不清楚。在特定目的I中，我们计划检验以下假设：凋亡SMC通过推动骨髓衍生的细胞募集刺激再生皮层化，这反过来又通过分化或旁分泌作用有助于内皮再生。我们还将测试CXCL7是否构成亲内皮细胞的募集。在特定的目标II中，我们将测试表达PKCD SMC产生的旁分泌作用是否是凋亡细胞的一般特性。在体外，我们将检查凋亡的诱导是否具有物理相关刺激（例如氧化应激）和细胞因子会产生旁分泌因子，从而吸引晚期成纤维细胞或骨髓衍生的循环促促促血管生成细胞。在体内，我们将驱动动脉平滑肌细胞到凋亡B表达人二骨毒素受体，并期望增强的凋亡将降低SMC加速度，刺激晚期成纤维细胞的迁移，但加速了再粘膜化。在特定的目标III中，我们将尝试翻译我们在初步研究中开发的PKCD修饰，以通过刺激细胞凋亡和重新内皮化但抑制晚期成纤维细胞的影响来减轻内膜增生。总而言之，这是一个重要且高度转化的项目，很可能会扩大我们对细胞死亡和治疗发展的了解。