Genetic mapping of variable cardiac cell composition in the rat

项目总结 在人类中，对心肌梗死等心脏损伤的生理反应是高度可变的。 新出现的文献已经确定了几种类型的心脏细胞，它们被认为可以保护个人免受不利影响 损伤后的转归，甚至促进一定程度的心肌再生。具体来说，频率 稳定状态心肌中单核二倍体心肌细胞的数量与改善预后相关 在小鼠模型中跟踪MI。此外，新出现的证据表明，心脏常驻 在心脏损伤的背景下，巨噬细胞群体促进修复性愈合。重要的是，其中的每一个 细胞类型在损伤前存在于稳定状态的心脏中，以不同的频率存在于 基因近亲繁殖的啮齿动物品系，很容易量化。因此，这些容易量化的特征允许 全基因组关联研究(GWAS)，以确定与心脏损伤和组织弹性相关的基因 再生。事实上，最近对近交系小鼠品系的研究，杂交小鼠的多样性 小组(HMDP)，正是实现了心脏再生的目标。在这里，我们建议扩展这一概念 最近在小鼠中实现了单一细胞类型，在大鼠中实现了多种细胞类型，其中有几种 比鼠标更有优势。首先，在许多情况下，老鼠的生理学更接近于 这表明这种遗传模型可能是一种更可靠的临床前模型。第二， 相当于近交系大鼠的集合，被称为杂交大鼠多样性小组(HRDP)，目前正在 在我们的机构(威斯康星医学院)重新衍生。最重要的是，HRDP显示 整个面板的遗传多样性大大增加，但具有与老鼠相同的作图能力 等同的，这表明可以利用老鼠将更多的基因座映射到数量性状上。在此，我们建议 使用HRDP进行基于GWAS的定位，以确定潜在的候选基因频率 单核二倍体心肌细胞(AIM 1)和组织驻留心肌巨噬细胞(AIM 2)的频率 稳定状态的心脏。这两个目标都将测试这两个细胞群体的不同频率对 心脏生理动态平衡与抗心肌梗死损伤。值得注意的是，机械论的见解 从这里识别的基因得出的结果可以应用于推进心脏再生策略，预测 对心力衰竭进展的易感性，以及为心力衰竭患者开发个性化治疗。

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.