Paracrine Regulation of Heart Failure

心力衰竭的旁分泌调节

基本信息

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
项目类别：
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

项目摘要

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，心脏会分泌因子来维持其性能并协调细胞活动以应对压力/或损伤。总的来说，我们将这些心脏分泌的因子称为心肌因子。心肌因子的鉴定和研究具有重要意义，因为它将提供有关心脏内组织间通讯的信息，并且这些分泌的因子可能具有有用的治疗或诊断功能。通过高通量转录本分析，我们鉴定出分泌型糖蛋白 Follistatin-like 1 (Fstl1)，也称为 TSC36 和 FRP，是一种新型心肌因子。我们证明 Fstl1 因心脏应激（包括缺血再灌注损伤、压力超负荷和永久性左冠状动脉前降支 (LAD) 结扎）而显着上调。我们最近表明，Fstl1 的急性过度表达将保护心脏免受缺血再灌注损伤，并促进小鼠模型缺血后肢的血运重建。然而，Fstl1 在心肌梗塞后 (MI) 心脏重塑中的功能作用尚不清楚，也不知道心脏中不同细胞类型产生的 Fstl1 如何影响重塑过程。在与临床实验室的合作中，我们发现可以在人血清中检测到 Fstl1，这些水平可以预测急性冠脉综合征或心力衰竭患者的临床结果。我们在实验模型中的初步工作表明，Fstl1 诱导发生在心肌细胞和巨噬细胞中，这表明 Fstl1 参与心肌细胞-巨噬细胞串扰，协调心力衰竭中的伤口愈合反应。在这里，我们将评估肌细胞来源的 Fstl1 与巨噬细胞来源的 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，临床数据显示这两个因素参与“生物标志物网络”，强调了其重要性。最后，我们将研究 Dip2a（一种最近鉴定的 Fstl1 受体分子）在介导 Fstl1 对心脏的心脏保护作用中的作用。为了评估 Fstl1 在这些过程中的作用，我们将采用已创建的新型条件敲除和过表达模型对于这些研究。