Genetic mapping of variable cardiac cell composition in the rat

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PROJECT SUMMARY The physiological response to cardiac injury such as myocardial infarction is highly variable in humans. Emerging literature has identified several cardiac cell types that are thought to protect individuals from adverse outcomes following injury, and even promote some degree of myocardial regeneration. Specifically, frequency of mononuclear diploid cardiomyocytes in the steady state myocardium correlates with improved outcomes following MI in the mouse model. Furthermore, emerging evidence demonstrates that cardiac resident macrophage populations promote reparative healing in the context of cardiac injury. Importantly, each of these cell types are present in the steady state heart prior to injury, are present at variable frequencies across genetically inbred rodent strains, and are easily quantifiable. Thus, these easily quantifiable traits allow for genome wide association studies (GWAS) to identify genes linked to resilience to cardiac injury and tissue regeneration. Indeed, recent work across a collection of inbred mouse strains, the Hybrid Mouse Diversity Panel (HMDP), achieved exactly this goal for heart regeneration. Here, we propose to expand this concept recently implemented in a single cell type in the mouse to multiple cell types in the rat, which has several advantages over the mouse. First, there are numerous situations where rat physiology more closely resembles that of humans, suggesting this genetic model could be a more faithful pre-clinical model. Second, the equivalent collection of inbred rats, known as the Hybrid Rat Diversity Panel (HRDP), is currently being rederived here at our institution (Medical College of Wisconsin). Most importantly, the HRDP displays substantially greater genetic diversity across the panel, but with the same mapping power as the mouse equivalent, suggesting more loci can be mapped to the quantitative trait using the rat. Here, we propose to perform GWAS-based mapping using the HRDP to identify candidate genes underlying the frequency of mononuclear diploid cardiomyocytes (Aim 1) and frequency of tissue resident cardiac macrophages (Aim 2) in the steady state heart. Both aims will test the effect of variable frequency of these two cell populations on cardiac physiological homeostasis and resistance to myocardial infarction injury. Notably, mechanistic insights resulting from genes identified here could be applied to advancing cardiac regeneration strategies, predicting susceptibility to heart failure progression, and developing personalized treatments for heart failure patients.