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Using colloborative cross mice to monitor resilience to malaria

使用协作交叉小鼠监测对疟疾的抵抗力

基本信息

批准号：
9982778
负责人：
David S. Schneider
金额：
$ 23.64万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982778
关键词：
Anemia Animals Biological Markers Blood Glucose C57BL/6 Mouse Cells Cerebral Malaria Child Collection Complex Control Locus Data Disease Disease Outcome Drug Targeting Elasticity Endemic Diseases Ensure Enzymes Exhibits Flow Cytometry Future Genetic Genetic Polymorphism Genetic Screening Genetic Variation Genotype Goals Grain Health Health Benefit Human Immune Immune response Inbred Mouse Inbred Strains Mice Individual Infection Inflammation Intervention Investigation Liver Malaria Maps Measurement Measures Metabolic Metabolic acidosis Methodology Methods Minority Modeling Molecular Probes Monitor Mouse Strains Mus Outcome Parasites Parents Pathogenesis Pathology Patients Pattern Phenotype Physiology Plasmodium Plasmodium chabaudi Population Probability Public Health Recovery Severities Severity of illness Signal Pathway Stretching Symptoms Syndrome System Temperature Testing Variant Weight Work cytokine experimental study improved innovation liver injury malaria infection molecular marker mortality mouse model natural hypothermia offspring pathogen pressure resilience response symptom cluster symptomatic improvement

项目摘要

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.

我们的首要目标是提高我们对感染的抵御能力。这将限制我们当我们生病时，我们会受苦，并将确保我们从感染中恢复。我们关注疟疾因为这种疾病仍然是严重的人类健康问题。疟疾导致数百人患病每年有数百万儿童死亡，数十万人死亡。疟疾有这么高的绝对死亡率，因为它感染了这么多，即使大多数儿童是抵抗感染的能力而不是试图消除这数亿人为了减少疟疾感染，我们正集中精力设法提高疟疾最严重受害者的复原力。我们的计划是通过使用小鼠疟疾来重现这种变异，模型我们计划用夏氏疟原虫感染小鼠，合作交叉，显示不同的症状，因为集合包含了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以鉴定严重病理的生物标志物。在未来，我们将尝试操纵这些生物标志物来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个父母的分析，合作杂交，发现它们对这种病原体的反应不同，我们可以发现与疾病严重程度相关的代谢物。我们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。我们还监测了492只夏氏疟原虫感染的多样性远交小鼠。这些老鼠是协作交叉我们发现，DO小鼠种群具有细粒度的连续性，疟疾的表型，我们可以绘制三个基因座，控制贫血，生存和由这种感染引起的体温过低。这些结果表明，在这个老鼠种群中，对疟疾的反应有相当大的遗传变异，我们可以仅使用8种小鼠品系就发现了显著的生物标志物命中，并且其中一些命中可以使用来改变疾病的结果。我们在这个提案中的目标是增加小鼠品系的数量我们可以通过识别沿着沿着所有疟疾表型。这将增加我们的分析能力，因为我们试图鉴定生物标志物和用于发病机理的药物靶点。