Using colloborative cross mice to monitor resilience to malaria

我们的首要目标是提高我们对感染的适应能力。这将限制我们的病理 当我们生病时，我们会遭受痛苦，并将确保我们从感染中康复。我们关注的是疟疾 因为这种疾病仍然是一个严重的人类健康问题。疟疾在数百人中引发疾病 每年数以百万计的儿童死亡，数十万人死亡。 疟疾的绝对死亡率如此之高，是因为它感染了这么多人，尽管大多数儿童都是 对感染有弹性的。与其试图消除这些数以亿计的 在防治疟疾感染方面，我们正集中精力研究如何提高疟疾病情最严重的受害者的复原力。 我们的计划是通过用小鼠疟疾重建这种变异来了解弹性是如何变化的 模特。我们计划用查鲍迪疟原虫感染小鼠，并从 表现出不同症状的协作性交叉，因为集合包含广泛的 遗传变异。然后我们将通过感染和代谢物将免疫反应联系起来。 在病理高峰期确定严重病理的生物标记物。在未来，我们将尝试 操纵这些生物标志物以确定哪些可以作为改变病理的杠杆。我们 有初步数据支持我们的方法。我们已经完成了对8名儿童父母的分析 合作交叉，发现它们对这种病原体的反应不同，我们可以 寻找与疾病严重程度相关的代谢物。我们已经调节了其中三种代谢物 以及它们的信号通路，并发现它们可以改变感染的结果。我们还有 监测了492只查鲍迪疫霉感染多样性杂交系小鼠。这些老鼠是 协作型交叉。我们发现DO小鼠群体有一个细粒度的连续体 疟疾的表型，我们可以定位三个控制贫血、存活率和 由这种感染引起的体温过低。总而言之，这些结果表明 在这个小鼠群体中，对疟疾的反应存在相当大的遗传变异，我们可以 仅使用8个小鼠品系即可找到重要的生物标记物，其中一些可用于 来改变疾病的结果。我们在这个提案中的目标是增加老鼠品系的数量 我们可以在分析中使用，方法是确定沿 各种疟疾表型。这将增加我们分析的力量，因为我们试图 确定发病机制的生物标志物和药物靶点。

Our overarching goal is to improve our resilience to infections. This will limit the pathology we suffer when we get ill and will ensure that we recover from our infections. We focus on malaria because this disease remains a serious human health problem. Malaria causes disease in hundreds of millions of children each year and kills hundreds of thousands. Malaria has this high absolute mortality because it infects so many, even though most children are resilient to the infection. Rather than trying to eliminate these hundreds of millions of infections, we are concentrating on ways of increasing resilience among malaria’s sickest victims. Our plan is to understand how resilience varies by recreating this variation using a mouse malaria model. We plan to infect mice with Plasmodium chabaudi and to identify mouse strains from the collaborative cross that show different symptoms because the collection contains a broad range of genetic variation. We will then correlate the immune response through the infection and metabolites at peak pathology to identify biomarkers for severe pathology. In the future, we will try manipulating these biomarkers to determine which can serve as levers for altering pathology. We have preliminary data supporting our approach. We’ve completed an analysis of the 8 parents of the collaborative cross and find that they differ in their response to this pathogen and that we can find metabolites that correlate with disease severity. We’ve modulated three of these metabolites and their signaling pathways and find that they can alter the outcome of infections. We have also monitored 492 P. chabaudi infected diversity outbred mice. These mice are the offspring of the collaborative cross. We found that the DO mouse population has a fine-grained continuum of phenotypes for malaria and that we can map three loci that control the anemia, survival and hypothermia resulting from this infection. Together these results suggest that there is considerable genetic variation in the response to malaria in this mouse population, that we can find significant biomarker hits using only 8 mouse strains, and that some of these hits can be used to modify disease outcomes. Our goal in this proposal is to increase the number of mouse strains we can use in our analysis by identifying collaborative cross lines that are spread out along the full range of malaria phenotypes. This will increase the power of our analyses as we try to identify biomarkers and drug targets for pathogenesis.