Genetic mapping of variable cardiac cell composition in the rat

项目摘要 对心脏损伤如心肌梗死的生理反应在人类中是高度可变的。 新兴的文献已经确定了几种被认为可以保护个体免受不良反应的心脏细胞类型。 损伤后的结果，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的结局相关 在小鼠模型中的MI之后。此外，新出现的证据表明， 巨噬细胞群促进心脏损伤背景下的修复性愈合。重要的是，每一个 细胞类型存在于损伤前的稳定状态心脏中，以不同的频率存在于不同的细胞类型中。 基因近交的啮齿动物品系，并且容易量化。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恢复力相关的基因 再生事实上，最近在一系列近交系小鼠品系上的工作， Panel（HMDP），实现了心脏再生的这一目标。在这里，我们建议扩展这一概念 最近在小鼠中的单一细胞类型中实施到大鼠中的多种细胞类型，其具有几个 鼠标的优势。首先，在许多情况下，大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。二是 目前，一个被称为杂交大鼠多样性小组（HRDP）的近交系大鼠的等效集合正在进行中。 在我们的机构（威斯康星州医学院）重新派生。最重要的是，HRDP显示 整个小组的遗传多样性大大增加，但与小鼠具有相同的映射能力 等效，表明更多的基因座可以映射到数量性状使用大鼠。在此，我们建议 使用HRDP进行基于GWAS的作图，以识别潜在的候选基因， 单核二倍体心肌细胞（目标1）和组织驻留心脏巨噬细胞的频率（目标2） 稳态心脏这两个目标都将测试这两个细胞群的可变频率对细胞增殖的影响。 心脏生理稳态和抵抗心肌梗死损伤。值得注意的是， 从这里发现的基因中产生的结果可以应用于推进心脏再生策略，预测 心力衰竭进展的易感性，并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.