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

• 批准号: 7676354
• 负责人: Thomas LaRocca
• 金额: $ 2.76万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-14 至 2012-05-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676354
• 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; Figs - dietary; Future; Gene Transfer; Generations; Genes; Goals; Growth; 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; 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; public health relevance; repaired; research study; response; response to injury; stem cell therapy; vector

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 CXCL12（也称为基质细胞衍生因子-1，SDF-1）及其主要受体 CXCR4 已被描述在干细胞募集至心肌区域中发挥关键作用梗塞（ML）。缺血组织中 CXCL12 表达的增加充当细胞信号，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，所有这些都会导致整体心脏功能的保存。然而，干细胞分化成新的心肌细胞以提供益处的主要假设在很大程度上尚未得到证实。这导致人们对鉴定心肌干细胞的旁分泌机制越来越感兴趣。研究表明，CXCL12 在各种类型干细胞中的过度表达不仅可以通过血管生成和抗凋亡机制，还可以通过抑制心肌重塑来增强 Mi 后的心脏性能。因此，该提案的直接目标是研究干细胞分泌因子CXCL12在心肌细胞重塑机制中的作用。该提案将重点关注去氧肾上腺素（PE）诱导的病理性肥大模型。因此，我们的假设需要 CXCL12 通过有益的抗重塑机制来预防 PE 诱导的心肌细胞病理性肥大。 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 CXCL12/CXCR4 轴是否是调节体外 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 CXCL12 对舒张期钙积累的影响。 2）我们将研究CXCL12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GSK3B。 3）我们将定义心脏CXCR4的过度表达和消融对PE诱导的体内肥大的生理后果。腺相关病毒9（AAV9）将被用作载体来进行CXCR4的过表达心肌基因转移。心脏功能和结构将通过体内血流动力学、ANF/BNP表达、心脏重量:体重比和组织学进行评估。公共健康相关性：该提案的结果将为了解 CXCR4 对心肌重塑的新调节机制提供见解。对成人心肌细胞中 CXCR4 信号传导的进一步研究可能有助于产生和完善基于干细胞的心脏病治疗新方法。