权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.