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，通过该机制，骨髓源性干细胞/祖细胞（BMSPCs）被动员到缺血心肌并促进心肌再生。虽然心肌梗死后BMSPC动员的大小与心脏恢复相关，但驱动BMSPC动员和归家的分子事件尚不清楚。长期的研究目标是为开发新的临床有用的心肌再生疗法来治疗AMI引起的损伤做出贡献。本应用的目的是确定生物活性脂质在AMI后BMSPCs向心肌的动员和归巢中的作用及其治疗效用。核心假设是，生物活性脂质在AMI后BMSPCs的动员和归巢中发挥重要作用，可用于临床促进心脏恢复。这项研究的基本原理是，它的完成有望为增强BMSPCs向损伤心肌的动员和归巢以促进AMI后的组织再生提供新的方法。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来验证：1)建立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)制定与临床相关的策略以提高

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.