A Systems Biology Approach to the Model Apicomplexan Toxoplasma gondii

弓形虫顶复门模型的系统生物学方法

基本信息

批准号：
8048844
负责人：
Kami Kim
金额：
$ 563.02万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048844
关键词：
Acquired Immunodeficiency Syndrome Affect Animal Model Apicomplexa Area Binding Biological Models C-terminal Categories Cessation of life Chromatin Cloning Collection Communicable Diseases Communities Complementary DNA Complex Congenital Abnormality Cryptosporidium DNA Binding DNA Binding Domain Data Data Set Development Diabetes Mellitus Disease Disease Outbreaks Drug Delivery Systems Environment Epidemic Epigenetic Process Epitopes Essential Genes Eukaryotic Cell Functional disorder Gene Activation Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genome Genomics Goals Human Immunocompromised Host Individual Knock-out Ligation Macromolecular Complexes Malaria Medical Metabolism Mining Modeling Molecular Biology Parasites Pathology Plasmodium Population Protein Binding Proteins Proteomics Public Health Resources Specificity System Systems Biology Testing Toxoplasma Toxoplasma gondii Transcription factor genes Translating Vaccines Virulence base biodefense combinatorial disorder prevention epigenomics expression vector genome sequencing genome-wide global health high throughput technology human disease innovation insight multidisciplinary novel obligate intracellular parasite pathogen prevent protein expression public health relevance response trait transcription factor treatment strategy waterborne

项目摘要

DESCRIPTION (provided by applicant): This application focuses upon the Apicomplexa, etiologic agents of many diseases in the developing world and relevant to global health (thematic area 4). It uses genomics and other high throughput technologies (thematic area 1) with a systems-level integration, analysis and mining of large datasets with the overarching goal of translating our discoveries into new insights into therapy and disease prevention (thematic area 2). To accomplish our goals, we have assembled a multidisciplinary collaborative team with expertise in infectious diseases, diabetes, metabolism, pathology, molecular biology, animal models and pathophysiology to conduct an innovative study in challenging biomedical areas (thematic area 5). As major emerging and reemerging pathogens, Apicomplexan parasites infect more than a third of the world's population. These obligate intracellular parasites include Toxoplasma gondii, Plasmodium species and Cryptosporidium. Toxoplasma gondii is a major opportunistic pathogen of the AIDS epidemic, a cause of birth defects and is also a Category B priority agent due to its association with waterborne outbreaks. Plasmodium species, the agents of malaria, infect over 267 million people per year and cause nearly 1 million deaths per year. Despite the importance of these parasites in human disease, there are no effective vaccines for these pathogens, and new strategies for treatment and prevention of disease are needed. Very little is understood how the Apicomplexa regulate virulence traits and respond to changes in their environment. The development of new high-throughput technologies has enabled collection of large genomic and proteomics datasets. These can be used to develop an integrated understanding of how eukaryotic cells regulate gene expression. We will take advantage of genome manipulation, genome-wide arrays, high throughput sequencing, and proteomics to develop datasets that will facilitate an integrated systems approach to understanding regulation of gene expression and epigenetics in the model apicomplexan T.gondii. We will test the essentiality of chromatin remodellers and candidate transcription factors using a moderate through-put gene disruption strategy. Using epitope tagged chromatin remodelers and transcription factors, we will use high throughput sequencing of chromatin immunoprecipitates and expression microarrays to identify groups of co-regulated genes. Finally, we will perform high-throughput proteomics to characterize the constituents of macromolecular complexes involved in regulation of gene expression. These epigenomic, transcriptome, and proteomic datasets will facilitate computational approaches to model how epigenetic and genetic factors in the Apicomplexa interact within gene networks. This effort will create important community resources to enable a systems biology approach toward understanding expression of virulence traits and identification of novel drug targets for apicomplexan parasites. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii is a parasitic pathogen that causes severe disease in immunocompromised individuals including people with AIDS, causes birth defects, and is a Biodefense Category B pathogen due to its association with waterborne outbreaks. Finally it is a model system for other parasites like Plasmodium, which cause human malaria. These parasites affect over a third of the world's population. We are trying to generate large datasets that will help us understand how these parasitic pathogens change in response to interaction with human hosts and how they regulate genes that cause disease. These data take advantage of genome sequencing projects and will use new powerful high throughput technologies. Gathering these data will be important for developing new treatments that will prevent T. gondii from persisting in infected people, and understanding how Apicomplexan parasites cause disease.

描述（由申请人提供）：本申请重点关注顶复门，这是发展中国家许多疾病的病因，且与全球健康相关（主题领域 4）。它使用基因组学和其他高通量技术（主题领域 1），对大型数据集进行系统级集成、分析和挖掘，总体目标是将我们的发现转化为治疗和疾病预防的新见解（主题领域 2）。为了实现我们的目标，我们组建了一支拥有传染病、糖尿病、代谢、病理学、分子生物学、动物模型和病理生理学专业知识的多学科协作团队，在具有挑战性的生物医学领域（主题领域5）开展创新研究。作为主要的新出现和重新出现的病原体，顶复门寄生虫感染了世界三分之一以上的人口。这些专性细胞内寄生虫包括弓形虫、疟原虫和隐孢子虫。弓形虫是艾滋病流行的主要机会病原体，是导致出生缺陷的原因，并且由于与水传播疾病的爆发有关，因此也是 B 类优先病原体。疟原虫是疟疾的病原体，每年感染超过 2.67 亿人，并导致近 100 万人死亡。尽管这些寄生虫在人类疾病中很重要，但目前还没有针对这些病原体的有效疫苗，因此需要新的治疗和预防疾病的策略。人们对顶复门如何调节毒力特征并对环境变化做出反应知之甚少。新的高通量技术的发展使得大型基因组和蛋白质组数据集的收集成为可能。这些可用于全面了解真核细胞如何调节基因表达。我们将利用基因组操作、全基因组阵列、高通量测序和蛋白质组学来开发数据集，以促进综合系统方法来理解弓形虫模型中基因表达和表观遗传学的调控。我们将使用中等通量的基因破坏策略来测试染色质重塑剂和候选转录因子的重要性。使用表位标记的染色质重塑剂和转录因子，我们将使用染色质免疫沉淀物的高通量测序和表达微阵列来识别共同调控的基因组。最后，我们将进行高通量蛋白质组学来表征参与基因表达调控的大分子复合物的成分。这些表观基因组、转录组和蛋白质组数据集将有助于计算方法来模拟 Apicomplexa 中的表观遗传和遗传因素如何在基因网络内相互作用。这项工作将创造重要的社区资源，使系统生物学方法能够理解毒力特征的表达并识别顶复门寄生虫的新药物靶点。公共卫生相关性：弓形虫是一种寄生病原体，会导致免疫功能低下的个体（包括艾滋病患者）患严重疾病，导致出生缺陷，并且由于与水传播疾病爆发有关，因此属于生物防御 B 类病原体。最后，它是其他寄生虫（例如引起人类疟疾的疟原虫）的模型系统。这些寄生虫影响着世界三分之一以上的人口。我们正在尝试生成大型数据集，以帮助我们了解这些寄生病原体如何因与人类宿主的相互作用而发生变化，以及它们如何调节导致疾病的基因。这些数据利用了基因组测序项目，并将使用新的强大的高通量技术。收集这些数据对于开发新的治疗方法非常重要，以防止弓形虫在感染者体内持续存在，并了解顶复门寄生虫如何引起疾病。