Unbiased Forward Genetic Analysis of Virus/Host Interactions

病毒/宿主相互作用的无偏正向遗传分析

基本信息

批准号：
7936279
负责人：
Malak Y.S. Kotb
金额：
$ 43.63万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-26 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936279
关键词：
Affect Animals Antiviral Agents Bacteria Bioinformatics Biological Biological Markers Blepharitis Body Surface Breeding Cause of Death Cells Cessation of life Chronic Communicable Diseases Complex Computers Cornea Coupled DNA Data Development Disease Disease Resistance Disease susceptibility Encephalitis Exhibits Experimental Designs Eye diseases Genes Genetic Genomics Histologic Human Immune response Inbred Mouse Inbred Strain Inbred Strains Mice Individual Infection Infectious Agent Inflammation Internet Iris Keratitis Knowledge Maps Measurement Medical Mining Modeling Molecular Profiling Mus Neuraxis Neurons Organism Outcome Parasites Pathogenesis Pathology Pathway interactions Peripheral Peripheral Nervous System Phase Phenotype Physicians Population Population Heterogeneity Predisposition Prevention strategy Process Property Proteomics Quantitative Trait Loci RNA Recombinant Inbred Strain Recombinants Recurrent disease Regulatory Pathway Relative (related person)Research Research Personnel Resistance Resistance to infection Risk Assessment Science Scientist Severities Severity of illness Siblings Simplexvirus Staging Stress Surface System Systems Biology Techniques Technology Translating Viral Viral Pathogenesis Virulence Virus Virus Diseases anterior chamber antimicrobial antimicrobial drug base cell type comparative database of Genotypes and Phenotypes disease phenotype fungus genetic analysis genetic element improved in vivo insight latent infection mathematical model mutant novel pathogen positional cloning programs protein expression public health relevance response trait treatment strategy virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Systems biology, "the sciences of the 21st century", is an interdisciplinary challenge for biologists, computer scientists, system theoreticians, and physicians. The "Systems" approach aims to capitalize on the dramatic advances in proteomics, genomics, and measurement technologies such as DNA arrays to generate a holistic understanding of biological organisms. Systems biology approaches can be profitably exploited to investigate the interaction of pathogens with their hosts. An essential first step is to identify host and pathogen genetic traits that contribute to important disease properties such as virulence. Forward genetic approaches permit the unbiased identification of Quantitative Trait Loci (QTL) of the host. The identification of potential relevant genes and pathways within QTL can then be integrated into high throughput experimental designs to identify RNA and protein expression profiles coupled with mathematical modeling and bioinformatics to assemble refined testable models of pathogenesis. Further refinement of the models is expected to yield insights into potential new preventative and treatment options, biomarkers predictive of disease susceptibility and severity, and importantly, personalized medical risk assessment and treatment strategies. At UC and CCHMC we have established strong programs in systems biology, an important new aspect of which is the establishment of a colony of the C57Blk/6xDBA/2 Advanced Recombinant Inbred strains. Thus we have >100 lines of fully genetically characterized ARI mice. Over the past 2 decades we have developed and characterized murine models of all facets of herpes simplex virus (HSV) pathobiology, pioneered strategies to quantify disease processes at the singe cell level and generated a large stable of defined viral mutants. We will combine these approaches in an unbiased forward "Systems Genetics" approach to identify host genes and pathways that moderate all phases of viral pathogenesis. This approach will identify common pathways and networks that affect disease severity that are anticipated to translate directly into improved individualized treatment and prevention strategies for viral infections in general, and reveal biomarkers and potential targets shared by many viral pathogens. PUBLIC HEALTH RELEVANCE: Infections by bacteria, viruses, fungi, and other parasites cause death in an estimated 17 million individuals per year worldwide. There is a great need for the identification of new targets that could provide the basis for the development of novel broad spectrum antimicrobial agents. The proposed research will use a forward genetic analysis to identify the network of host pathways regulating disease susceptibility and resistance. This information will identify potential targets for broad spectrum antimicrobial agents.

描述（由申请人提供）：系统生物学，“ 21世纪的科学”，是生物学家，计算机科学家，系统理论家和医师的跨学科挑战。 “系统”方法旨在利用蛋白质组学，基因组学和测量技术（例如DNA阵列）的巨大进步，以产生对生物生物体的整体理解。可以利用系统生物学方法来研究病原体与宿主的相互作用。重要的第一步是识别有助于毒力等重要疾病特性的宿主和病原体遗传特征。正向遗传方法允许对宿主的定量性状基因座（QTL）公正地识别。然后，可以将QTL内潜在相关基因和途径的鉴定整合到高吞吐实验设计中，以鉴定RNA和蛋白质表达谱，并结合数学建模和生物信息学，以组装可得到的可测试模型的发病机理。预计该模型的进一步完善有望深入了解潜在的新预防和治疗选择，生物标志物可以预测疾病易感性和严重性，重要的是，个性化的医疗风险评估和治疗策略。在UC和CCHMC，我们在系统生物学方面建立了强大的计划，其中一个重要的新方面是建立C57BLK/6XDBA/2高级重组近交菌株的菌落。因此，我们拥有> 100行完全遗传表征的ARI小鼠。在过去的20年中，我们已经开发并表征了单纯疱疹病毒（HSV）病理生物学的所有方面的鼠模型，这是量化单个细胞水平上疾病过程的开创性策略，并产生了大量的定义病毒突变体。我们将将这些方法结合在公正的前进“系统遗传学”方法中，以识别适度病毒发病机理所有阶段的宿主基因和途径。这种方法将确定影响疾病严重程度的通用途径和网络，这些途径和网络通常会直接转化为一般的病毒感染的个性化治疗和预防策略，并揭示许多病毒病原体共有的生物标志物和潜在靶标。公共卫生相关性：细菌，病毒，真菌和其他寄生虫的感染在全球范围内估计有1700万人死亡。非常需要鉴定新目标，这可以为开发新型广谱抗菌剂提供基础。拟议的研究将使用远期遗传分析来确定调节疾病易感性和抗性的宿主途径网络。该信息将确定广谱抗菌剂的潜在靶标。