Role of bioactive lipids in the protective pathways of obesity in ischemic cardi

肥胖在西方世界正接近流行状态，是急性心肌梗死的已知危险因素 心肌梗死(AMI)。急性心肌梗死和随后的缺血性心脏病(IHD)常合并高血压性心脏病 死亡率和总体预后较差，尽管在药物治疗和血管重建方面取得了重大进展 战略。目前，由于缺乏心脏移植的所有遗传局限性，目前还没有可用的 替代受累心肌的治疗策略和治疗在很大程度上是姑息性的。矛盾的是， 肥胖还可能对导致IHD的急性心肌梗死相关重塑起到保护作用。这个 对这种保护作用的分子克隆病知之甚少。急性心肌梗塞启动知之甚少的先天修复 骨髓间充质干细胞动员和归巢至缺血心肌的机制 有助于心肌再生，并与心脏恢复相关。我们的初步数据显示 生物活性脂质，如鞘氨醇-1磷酸(SIP)，而不是传统的趋化因子，发挥着 在这种动员和归宿中扮演着典型的角色。有趣的是，肥胖和相关的新陈代谢 综合征与生物活性脂类代谢的改变有关。我们在这项申请中的目标是， 因此，更好地了解肥胖相关的急性心肌梗死诱导的干细胞的变化 动员途径，特别是那些涉及生物活性脂质的途径，并设计出阻碍这一点的治疗方法 治疗心肌再生策略的过程。我们的中心假设已经公式化了 基于现有的文献和我们强有力的初步数据表明，BMSPC表达SIP 并将以SI P依赖的方式从急性心肌梗死患者向血浆迁移。我们的理由是 这些研究表明，了解生物活性脂质的保护作用和干细胞动员 肥胖的急性心肌梗死将有助于为最终可推广的人类建立一个强有力的科学框架 利用现有的和新的生物活性药物调节剂进行的心肌再生临床试验 脂类及其受体。除了临床研究，我们的方法还将利用小分子策略 通过研究肥胖相关的分子和细胞通路，特别是那些 涉及由心肌梗死激活的生物活性脂质(目标1)；并检查 促进急性心肌梗死后心脏恢复的生物活性脂类代谢和受体表达(目标2)。

Obesity is approaching epidemic state in the western worid and is a known risk factor for acute myocardial infarction (AMI). AMI and the subsequent ischemic heart disease (IHD) are often complicated with high mortality and poor overall prognosis despite significant advances in medical therapy and revascularization strategies. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infracted myocardium and therapies are largely palliative. Paradoxically, obesity may also confer a protective effect against AMI-associated remodeling which leads to IHD. The molecular kiasis for this protection is poorly understood. AMI initiates poorly understood innate reparatory mechanisms through which BMSPCs are mobilized and home towards the ischemic myocardium contributing to myocardial regeneration and correlating with cardiac recovery. Our preliminary data indicates that bioactive lipids such as sphingosine-1 phosphate (SIP), but not traditional chemokines, play a quintessential role in this mobilization and homing. Interestingly, obesity and the associated metabolic syndrome are associated with alterations in bioactive lipids' metabolism. Our objective in this application, therefore, is to develop better understanding ofthe obesity-associated alterations in AMI-induced stem cell mobilization pathways, specially those involving bioactive lipids, and devise therapies that hamess this process for therapeutic myocardial regeneration strategies. Our central hypothesis has been formulated based upon the existing literature and our strong preliminary data demonstrating that BMSPCs express SIP receptors and will migrate towards plasma from AMI patients in an SI P dependent fashion. Our rationale for these studies is that understanding the protective role of bioactive lipids and stem cell mobilization during AMI in obesity would help establish a strong scientific framework for eventual generalizable human myocardial regenerative clinical trials utilizing the available and new pharmacological modulators of bioactive lipids and their receptors. In addition to clinical studies, our approach will exploit small molecule-strategies in mouse models through examining the obesity associated molecular and cellular pathways, specially those involving bioactive lipids, that are activated by myocardial infarction (Aim 1); and examine the modulation of bioactive lipids' metabolism and receptor expression to enhance cardiac recovery following AMI (Aim 2).