Paracrine Regulation of Heart Failure

心力衰竭的旁分泌调节

• 批准号: 8723273
• 负责人: KENNETH WALSH
• 金额: $ 40.11万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723273
• 关键词: Acute; Address; Anterior Descending Coronary Artery; Biological Markers; Cardiac; Cardiac Myocytes; Cell Culture Techniques; Cells; Clinical; Clinical Data; Clinical Research; Communication; Cultured Cells; Data; Diagnostic; Disease Pathway; Dissection; Experimental Models; Follistatin; Follistatin-Like Protein 3; GDF15 gene; Genetic Models; Heart; Heart Diseases; Heart failure; Homeostasis; Human; In Vitro; Infarction; Inflammatory; Injury; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; Left; Left Ventricular Remodeling; Ligation; Limb structure; Link; Mediating; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Outcome; Patients; Performance; Process; Production; Proteins; Recruitment Activity; Regulation; Relative (related person); Reperfusion Injury; Role; Series; Serum; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Transcript; Work; Wound Healing; acute coronary syndrome; base; cell type; clinically relevant; in vivo; macrophage; mouse model; novel; overexpression; paracrine; pressure; prognostic; protein function; public health relevance; receptor; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): A growing body of evidence shows that the heart secretes factors to maintain its performance and coordinate cellular activities in response to stress/ or injury. Collectively, we refer to these cardiac-secreted factors as cardiokines. The identification and study of cardiokines is significant because it will provide information about intertissue communication within the heart, and these secreted factors may serve useful therapeutic or diagnostic functions. Via high throughput transcript analyses, we identified the secreted glycoprotein Follistatin-like 1 (Fstl1), also referred to as TSC36 and FRP, as a novel cardiokine. We demonstrated that Fstl1 is markedly upregulated by cardiac stress including ischemia-reperfusion injury, pressure overload and permanent left anterior descending coronary artery (LAD) ligation. We recently showed that acute overexpression of Fstl1 will protect the heart from ischemia-reperfusion injury and will promote revascularization of ischemic hind limbs in murine models. However, the functional role of Fstl1 in post- myocardial infarction (MI) cardiac remodeling is unknown, nor is it known how Fstl1 production by different cell types in the heart influence the remodeling process. In collaborative efforts with clinical laboratories we have found that Fstl1 can be detected in human serum, and these levels are prognostic for clinical outcomes in patients with either acute coronary syndrome or heart failure. Our pilot work in experimental models show that Fstl1 induction occurs both in cardiac myocytes and macrophages recruited to the infarct, suggesting that Fstl1 is involved in cardiac myocyte-macrophage crosstalk that coordinates the wound healing response in heart failure. Here we will evaluate the relative contributions of myocyte- versus macrophage-derived Fstl1 in post-MI remodeling. We will also explore the regulatory mechanisms and significance of Fstl1-mediated GDF15 regulation, whose importance is underscored by clinical data showing that these two factors participate in a "biomarker network." Finally, we will examine the role of Dip2a, a recentl identified Fstl1 receptor molecule, in mediating the cardioprotective actions of Fstl1 on the heart To assess the role of Fstl1 in these processes, we will employ novel conditional knockout and overexpression models that have been created for these studies.

描述（由申请人提供）：越来越多的证据表明，心脏分泌因应激/或伤害而保持其性能并协调细胞活动的因素。总的来说，我们将这些分泌的心脏分泌因子称为心脏动物。心脏代因的识别和研究很重要，因为它将提供有关心脏内部交流的信息，并且这些分泌的因素可能具有有用的治疗或诊断功能。通过高吞吐笔录分析，我们将分泌的糖蛋白卵蛋白类蛋白样1（FSTL1）（也称为TSC36和FRP）确定为一种新的心脏心。我们证明了FSTL1被心脏应激明显上调，包括缺血 - 再灌注损伤，压力超负荷和永久性左前冠状动脉（LAD）结扎。我们最近表明，FSTL1的急性过表达将保护心脏免受缺血 - 再灌注损伤，并将促进鼠模型中缺血性后肢的血运重建。但是，FSTL1在心肌梗死（MI）心脏重塑中的功能作用尚不清楚，也不知道它在心脏中不同细胞类型的FSTL1产生如何影响重塑过程。 在与临床实验室的合作中，我们 已经发现，可以在人血清中检测到FSTL1，并且这些水平是急性冠状动脉综合征或心力衰竭患者的临床结局的预后。我们在实验模型中的试验工作表明，FSTL1诱导既发生在梗死的心肌细胞和巨噬细胞中，这表明FSTL1参与心肌肌细胞巨噬细胞串扰，可以协调心脏衰竭中伤口愈合反应。在这里，我们将评估肌细胞与巨噬细胞衍生的FSTL1在MI后重塑中的相对贡献。我们还将探讨FSTL1介导的GDF15调节的调节机制和意义，其重要性是由临床数据强调的，表明这两个因素参与了“生物标志物网络”。最后，我们将研究DIP2A（最近鉴定出的FSTL1受体分子）在介导FSTL1在心脏上评估FSTL1在这些过程中的作用中的心脏保护作用的作用，我们将采用为这些研究创建的新型条件敲除和过表达模型。