Role of Bioactive Lipids in Stem Cell Mobilization and Homing in Cardiac Ischemia

描述（由申请人提供）：急性心肌梗死（AMI）启动先天免疫和修复机制，骨髓源性干/祖细胞（BMSPC）通过该机制被动员至缺血心肌并促进心肌再生。尽管AMI后BMSPC动员的程度与心脏恢复相关是清楚的，但驱动BMSPC动员和归巢的分子事件知之甚少。长期的研究目标是促进新的临床有用的心肌再生治疗急性心肌梗死造成的损伤的发展。本申请的目的是确定生物活性脂质在AMI后BMSPCs动员和归巢至心肌中的作用及其治疗效用。中心假设是生物活性脂质在AMI后BMSPCs动员和归巢中发挥重要作用，可用于临床以促进心脏恢复。提出的研究的基本原理是，它的完成有望提供新的方法，以加强动员和归巢的BMSPCs损伤心肌，以促进组织再生后AMI。在强有力的初步数据的指导下，这一假设将通过追求两个具体目标进行检验：1）确定生物活性脂质在急性心肌梗死后干细胞动员和归巢中的作用; 2）制定临床相关策略，以改善急性心肌梗死后干细胞的动员。 BMSPCs对急性缺血损伤后受损心肌的保护作用。在第一个目标下，该方法将涉及检查人类受试者和使用具有改变的生物活性脂质水平的转基因动物模型，以确定它们在BMSPC动员中的作用。对于第二个目的，该方法将需要使用临床相关的药理学试剂来调节生物活性脂质的作用，从而实现所需的BMSPC动员和归巢作用以及随后的心肌恢复。该方法具有潜在的创新性，因为它涉及利用生物活性脂质和免疫系统成员进行BMSPC动员和归巢，以提高AMI后患者的结局。拟议的研究是重要的，因为它预计将构成一个重要的第一步，在一个连续的研究，最终将导致改善机制为基础的心肌再生疗法。最终，这些知识有可能为最终开发治疗AMI诱导的心力衰竭的新机制策略做出有意义的贡献。

DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) initiates innate immune and reparatory mechanisms through which Bone marrow-derived stem/progenitor cells (BMSPCs) are mobilized towards the ischemic myocardium and contribute to myocardial regeneration. Although it is clear that the magnitude of BMSPC mobilization following AMI correlates with cardiac recovery, the molecular events driving BMSPC mobilization and homing are poorly understood. The long-term research goal is to contribute toward the development of new clinically useful myocardial regenerative therapies for injury caused by AMI. The objective for this application is to identify the role of bioactive lipids in the mobilization and homing of BMSPCs to the myocardium following AMI and their therapeutic utility. The central hypothesis is that bioactive lipids play an important role in BMSPCs mobilization and homing following AMI that can be utilized clinically to enhance cardiac recovery. The rationale for the proposed research is that its completion is expected to offer new methods for enhancing the mobilization and homing of BMSPCs to injured myocardium to promote tissue regeneration following AMI. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Establish the role of bioactive lipids in stem cell mobilization and homing after acute myocardial infarction; and 2) Develop clinically relevant strategies to improve the mobilization of BMSPCs to the injured myocardium following acute ischemic insult. Under the first aim, the approach will involve examining human subjects and the use of transgenic animal models with altered levels of bioactive lipids to determine their role in BMSPC mobilization. For the second aim, the approach will entail using clinically relevant pharmacological agents to modulate the effects of bioactive lipids and thereby achieve the desired BMSPC mobilization and homing effect and subsequent myocardial recovery. The approach is potentially innovative in that it involves utilizing bioactive lipids and members of the immune system in BMSPC mobilization and homing to enhance the outcomes of patients post AMI. The proposed research is significant because it is expected to constitute an important first step in a continuum of research that will ultimately lead to improved mechanism-based myocardial regenerative therapies. Ultimately, such knowledge has the potential to contribute meaningfully toward the ultimate development of novel mechanism-based strategies to treat AMI-induced heart failure.