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

Anti-Remodeling Effects of the CXCL12/CXCR4 Axis in the Cardiac Myocyte

CXCL12/CXCR4轴在心肌细胞中的抗重构作用

基本信息

批准号：
8066025
负责人：
Thomas LaRocca
金额：
$ 1.54万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-14 至 2011-11-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066025
关键词：
Address Adrenergic Agents Adult Apoptosis Apoptotic Area Autologous Basic Science Biological Preservation Body Weight CXCL12 gene CXCR4 Receptors CXCR4 gene Calcineurin Calcium Cardiac Cardiac Myocytes Cardiac ablation Cardiomyopathies Cardiovascular Diseases Cell Size Cell Therapy Cells Clinical Clinical Trials Complex Dependovirus Fibrosis Future Gene Transfer Generations Genes Goals Growth Health Healthcare Heart Heart Diseases Heart Hypertrophy Heart failure Histology Human Hypertrophy Immune In Vitro Incidence Individual Inflammation Injection of therapeutic agent Injury Investigation Laboratories Left Ventricular Hypertrophy Left Ventricular Remodeling MAPK14 gene MAPK3 gene MAPK8 gene Measures Messenger RNA Methods Microfilaments Mitogen-Activated Protein Kinases Modeling Molecular Mus Myoblasts Myocardial Myocardial Infarction Myocardium Natural regeneration Nature Nuclear Translocation Pathway interactions Patients Performance Phenylephrine Phosphorylation Physiological Play Protein Biosynthesis Reporting Role Signal Transduction Skeletal Myoblasts Somatic Gene Therapy Stem Cell Factor Stem cells Stress Stromal Cell-Derived Factor 1 Structure Technology Testing Therapeutic Tissues Ventricular Remodeling Weight adeno-associated viral vector adrenergic angiogenesis autocrine biological adaptation to stress calcineurin phosphatase cell injury cell type chemokine hemodynamics improved in vivo insight interest mRNA Expression novel strategies nuclear factors of activated T-cells overexpression paracrine prevent programs repaired research study response response to injury stem cell therapy vector

项目摘要

DESCRIPTION (provided by applicant): The chemokine, CXCL12 (also known as Stromal Cell Derived Factor-1, SDF-1) and its major receptor, CXCR4, have been described to play a critical role in recruitment of stem cells to areas of myocardial infarction (Ml). The increased expression of CXCL12 in ischemic tissue acts as a cellular signal to attract potentially beneficial stem cells to repair, and possibly regenerate, damaged myocardium by preventing apoptosis, inducing angiogenesis and inhibiting fibrosis, all leading to a preservation of global cardiac function. However, the main hypothesis of stem cells differentiating into new cardiac myocytes to provide benefit has been largely unproven. This has led to an increased interest in identifying paracrine mechanisms of stem cells in the myocardium. Studies have demonstrated overexpression of CXCL12 in various types of stem cells enhances cardiac performance post-Mi by not only angiogenic and anti-apoptotic mechanisms, but also through inhibition of myocardial remodeling. Therefore, the immediate goal of this proposal is to investigate the role of the stem cell secretory factor, CXCL12, on remodeling mechanisms in the cardiac myocyte. This proposal will focus on a phenylephrine (PE)-induced pathological hypertrophy model. Hence, our hypothesis entails CXCL12 preventing PE-induced pathological hypertrophy in the cardiac myocyte by a beneficial, anti-remodeling mechanism. 1) We will determine whether the CXCL12/CXCR4 axis is a molecular determinant in modulating PE-induced hypertrophic responses in the cardiac myocyte in vitro by assessing protein synthesis, ANF mRNA expression, myofilament organization and cell size. Next, the effect of CXCL12 on diastolic calcium accumulation will also be measured. 2) We will investigate the mechanism by which CXCL12 regulates PE-induced cardiac myocytehypertrophy, focusing on three major regulatory nodes of hypertrophy signaling: Calcineurin/NFAT, MAP Kinases, and GSK3B. 3) We will define the physiological consequences of the over-expression and ablation of cardiac CXCR4 on PE-induced hypertrophy in vivo. Adeno-associated virus-9 (AAV9) will be used as a vector to perform over-expression myocardial gene transfer of CXCR4. Cardiac function and structure will be assessed by in vivo hemodynamics, ANF/BNP expression, heart weight:body weight ratio, and histology. PUBLIC HEALTH RELEVANCE: The results from this proposal will provide insights into a new modulatory mechanism of CXCR4 upon myocardial remodeling. The further investigation of CXCR4 signaling in the adult cardiac myocyte may help in the generation and refinement of new approaches to stem cell based therapies for cardiac disease.

描述（由申请人提供）：趋化因子CXCL 12（也称为基质细胞衍生因子-1，SDF-1）及其主要受体CXCR 4已被描述为在将干细胞募集到心肌梗死（MI）区域中起关键作用。缺血组织中CXCL 12表达的增加作为细胞信号吸引潜在有益的干细胞通过防止细胞凋亡、诱导血管生成和抑制纤维化来修复并可能再生受损的心肌，所有这些都导致整体心脏功能的保护。然而，干细胞分化为新的心肌细胞提供益处的主要假设在很大程度上尚未得到证实。这导致了越来越多的兴趣，在确定旁分泌机制的干细胞在心肌。研究表明，在各种类型的干细胞中CXCL 12的过表达不仅通过血管生成和抗凋亡机制，而且通过抑制心肌重塑来增强Mi后的心脏性能。因此，本提案的直接目标是研究干细胞分泌因子CXCL 12在心肌细胞重塑机制中的作用。本建议将重点放在苯肾上腺素（PE）诱导的病理性肥大模型。因此，我们的假设需要CXCL 12通过有益的抗重塑机制来预防心肌细胞中PE诱导的病理性肥大。1)我们将通过评估蛋白质合成、ANF mRNA表达、肌丝组织和细胞大小来确定CXCL 12/CXCR 4轴是否是体外调节PE诱导的心肌细胞肥大反应的分子决定因素。接下来，还将测量CXCL 12对舒张期钙积累的影响。2)我们将研究CXCL 12调节PE诱导的心肌细胞肥大的机制，重点关注肥大信号传导的三个主要调节节点：钙调神经磷酸酶/NFAT，MAP激酶和GSK 3B。3)我们将定义心脏CXCR 4的过度表达和消融对体内PE诱导的肥大的生理后果。将使用腺相关病毒-9（AAV 9）作为载体进行CXCR 4的过表达心肌基因转移。将通过体内血流动力学、ANF/BNP表达、心脏重量：体重比和组织学评估心脏功能和结构。公共卫生相关性：该提案的结果将为CXCR 4对心肌重塑的新调节机制提供见解。对CXCR 4信号在成年心肌细胞中的进一步研究可能有助于产生和改进基于干细胞的心脏疾病治疗的新方法。