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Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction

溶血磷脂酸介导急性梗塞后的心脏炎症

基本信息

批准号：
10698647
负责人：
Ahmed Abdel-Latif
金额：
$ 20.77万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698647
关键词：
Lysophosphatidic Acid Mediates Cardiac Inflammation

项目摘要

PROJECT SUMMARY/ABSTRACT Ischemic heart disease is the leading cause of morbidity and mortality in the U.S. population and is often caused by acute myocardial infarction (AMI). AMI initiates an inflammatory response leading to increased circulating inflammatory bone marrow cells (BMCs), particularly monocytes (monocytosis). This response is crucial for removing dead tissue and initiating the healing process. However, exacerbated inflammatory response following AMI can be detrimental and is associated with infarct expansion, poor cardiac remodeling and adverse clinical outcomes. While most studies focus on monocyte production following AMI, the mechanism(s) of monocyte egress from the bone marrow and early cardiac infiltration after AMI are poorly understood. Our preliminary data demonstrate the role of the signaling bioactive lipid, lysophosphatidic acid (LPA), in the post-AMI mobilization of BMCs. LPA, produced by the enzyme autotaxin (ATX), plays a key role in activating inflammatory monocytes, regulating their peripheral blood count and homing them to sites of inflammation. Preliminary studies also indicated that LPA levels are elevated early in PB and cardiac tissues after AMI in humans and mice. The long- term goal is to contribute to development of new clinically useful therapies for AMI injury. The overall objective of this application is to define LPA mediated signaling pathways linking AMI to the inflammatory BM response. The rationale for the proposed research is its potential to offer new approaches to reduce inflammation and improve cardiac recovery after AMI. The central hypothesis is that LPA plays a key role in initiating and maintaining the post-AMI inflammatory response, thus impairing cardiac recovery. This hypothesis will be tested by pursuing three specific aims: 1) Identify the molecular mechanism(s) that result in elevated plasma LPA after AMI, 2) Determine the signaling systems by which ATX/LPA axis promotes monocytosis after AMI, and 3) define the association between LPA levels, heritable genetic variability in LPA receptor 1 that predicts receptor expression and monocytosis after AMI in humans. Results of these studies are expected to provide new mechanistic understanding of AMI-induced ATX/LPA signaling, their contribution to AMI-associated systemic monocytosis and cardiac inflammation and the role of heritable genetic mutations in monocytosis and inflammation in humans. To attain this goal, the proposed project will combine human studies with animal models with genetic manipulation of key components of the ATX/LPA signaling. This group has extensive experience in studying heart/BM signaling after AMI as well as ATX/LPA signaling pathways. The overall impact of these studies derives from an innovative focus on the ATX/LPA signaling nexus as a critical mechanism in AMI-induc ed inflammation and the potential to control post-AMI infarct expansion and subsequent heart failure by dampening this pathological response.

项目摘要/摘要缺血性心脏病是美国人口发病率和死亡率的主要原因，通常是由由急性心肌梗死(AMI)引起。急性心肌梗死引发炎症反应导致循环增加炎性骨髓细胞，特别是单核细胞(单核细胞增多症)。这一反应对以下方面至关重要移除死亡组织并启动愈合过程。然而，以下情况加剧了炎症反应急性心肌梗死可能是有害的，并与梗塞扩大、心脏重构不良和临床不良有关。结果。虽然大多数研究集中在急性心肌梗死后单核细胞的产生，但单核细胞的机制(S) 对急性心肌梗死后的骨髓渗出和早期心脏浸润性病变知之甚少。我们的初步数据证明信号生物活性脂质溶血磷脂酸(LPA)在急性心肌梗死后动员中的作用宝马汽车。LPA由自体趋化蛋白(ATX)酶产生，在激活炎性单核细胞方面发挥关键作用。调节他们的外周血细胞计数，并把他们送到发炎的地方。初步研究亦包括提示人和小鼠急性心肌梗死后早期外周血和心脏组织中LPA水平升高。长的- 长期目标是为开发新的临床有用的治疗急性心肌梗死损伤的方法做出贡献。总体目标这一应用的目的是确定LPA介导的信号通路，将急性心肌梗死与炎症性骨髓反应联系起来。这项拟议的研究的基本原理是它有可能提供新的方法来减少炎症和改善急性心肌梗死后的心脏恢复。中心假说是LPA在启动和维持急性心肌梗死后的炎症反应，从而损害心脏的恢复。这一假设将得到检验。通过追求三个特定的目标：1)确定导致血浆LPA升高的分子机制(S) 2)确定ATX/LPA轴促进急性心肌梗死后单核细胞增多的信号系统；3)确定 LPA水平与LPA受体1中预测受体的可遗传遗传变异性之间的关系人急性心肌梗死后的表达和单核细胞增多。这些研究的结果有望提供新的急性心肌梗死诱导的ATX/LPA信号机制及其在急性心肌梗死相关系统中的作用单核细胞增多症和心脏炎症以及可遗传基因突变在单核细胞增多症和心脏炎症中的作用人类的炎症。为了实现这一目标，拟议的项目将把人体研究与动物模型结合起来通过遗传操作ATX/LPA信号的关键成分。这个团队在以下方面有丰富的经验研究急性心肌梗死后心脏/骨髓信号转导及ATX/LPA信号转导途径。这些措施的总体影响研究源于对ATX/LPA信号联系作为急性心肌梗死诱导的关键机制的创新关注炎症和通过抑制抑制来控制急性心肌梗死后梗塞扩大和继发性心力衰竭的可能性这种病理性的反应。