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.
The proposed research is relevant to public health in that ischemic heart disease following AMI is the leading cause of mortality and morbidity in the United States. A mechanism-based understanding of how bioactive lipids mediate BMSPC mobilization and homing following acute ischemic cardiac injury is expected to contribute to a framework whereby novel therapeutic approaches can be developed. Thus, the proposed research is relevant to the part of the NIH's mission pertaining to developing and applying fundamental knowledge to protect and improve health.