Identification and Characterization of Pathology Minimization Mechanisms During I

I 期间病理最小化机制的识别和表征

• 批准号: 8648491
• 负责人: Damian Luis Trujillo
• 金额: $ 5.15万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648491
• 关键词: Acute; Affect; Attenuated; Biliverdine; Carbon Monoxide; Catabolism; Cells; ChIP-seq; Communicable Diseases; Data; Excision; Exhibits; Family; Family member; Gene Deletion; Generations; Genes; Genetic Transcription; Goals; Health; Health Care Costs; Heme; Hemolysis; Human; IRF3 gene; Immune response; Individual; Infection; Interferons; Knowledge; Lead; Malaria; Measures; Mediating; Methods; Microbe; Modeling; Monitor; Mus; Organism; Parasites; Parasitic infection; Pathogen detection; Pathology; Pathway interactions; Phase; Phenotype; Physiological; Plasmodium; Process; Proteins; Publishing; RNA; Relative (related person); Research; Resistance; Resistance to infection; Severities; Severity of illness; Testing; Therapeutic; Tissues; Wild Type Mouse; Work; analytical method; cytotoxic; experience; heme oxygenase-1; human IRF3 protein; interferon regulatory factor-3; microbial; novel; novel therapeutic intervention; pathogen; prevent; programs; public health relevance; response; therapy development; transcription factor; wasting

DESCRIPTION (provided by applicant): Organisms have two mechanisms to survive pathogenic infections: resistance and pathology minimization. Resistance is the ability to eliminate pathogens and we have a strong mechanistic understanding of how immune responses are initiated and executed. Contrary to this, we know of only a few mechanisms by which hosts minimize infection-associated damage irrespective of pathogen load. My goal is to identify and characterize mechanisms by which the host minimizes infection-associated damage. I hypothesize that hosts induce pathology minimization programs in response to pathogen detection and host damage. I will test and characterize how damage to the host (in the form of acute hemolysis) mediates pathology minimization upon subsequent Plasmodium infection. Hemolysis leads to the release of cytotoxic heme, which induces expression of host heme oxygenase-1 (HO-1). When mice are infected with plasmodium subsequent to constitutive low-level or acute hemolysis, these mice exhibit a diminished health impact in a HO-1 dependent manner. I would like to better characterize the reason for this diminished disease severity. I will do this by examining how HO-1-mediated heme catabolism minimizes pathology. I will also test whether the Interferon Regulatory Factor (IRF) proteins, a family of transcription regulators we've found to be induced upon Plasmodium infection, can mediate pathology minimization. We have chosen to focus on IRF proteins because published data suggests that IRFs, as well as IRF regulated genes, can limit the amount of pathology incurred in different types of infections. This will be done using a novel analytical method developed within the lab, termed phase curve analysis, which allows us to evaluate the health impact of microbes on individual hosts during the entire course of the infection. The work proposed here will be the first to systematically identify and characterize novel pathology minimization mechanisms. This proposal also aims to define how these mechanisms are induced. This knowledge may be key in understanding and developing inducible pathology minimization mechanisms as therapeutics for humans experiencing pathogenic infections. As there are many infectious diseases we cannot prevent, it is important that we are able to reduce the amount of damage incurred during these infections. Finally, the work proposed here will serve as a template for identifying mechanisms that may be employed to minimize the severity of unavoidable infections.

描述（由申请人提供）：生物体有两种机制来生存致病性感染：耐药性和病理最小化。耐药性是消灭病原体的能力，我们对免疫反应是如何启动和执行的机制有很强的了解。与此相反，我们只知道几种机制，通过这些机制，宿主可以将感染相关的损伤最小化，而不考虑病原体负荷。我的目标是识别和表征宿主将感染相关损伤最小化的机制。我假设宿主诱导病理最小化程序以响应病原体检测和宿主损伤。我将测试并描述宿主的损伤（以急性溶血的形式）如何在随后的疟原虫感染中介导病理最小化。溶血导致细胞毒性血红素的释放，从而诱导宿主血红素氧化酶-1 （HO-1）的表达。当小鼠在本构性低溶血或急性溶血后感染疟原虫时，这些小鼠表现出HO-1依赖方式的健康影响减弱。我想更好地描述疾病严重程度降低的原因。我将通过研究ho -1介导的血红素分解代谢如何使病理最小化来做到这一点。我还将测试是否干扰素调节因子（IRF）蛋白，一个家族的转录