Mechanisms of Stimulating Innate Immunity

刺激先天免疫的机制

基本信息

批准号：
9115045
负责人：
Natasha Kirienko
金额：
$ 10.8万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9115045
关键词：
Animal Model Antibiotic Therapy Antibiotics Antimicrobial Resistance Applications Grants Autoimmune Diseases Bacterial Infections Biological Biological Assay Biological Models Biology Caenorhabditis elegans Cellular Structures Chemicals Communicable Diseases Data Development Disease Drosophila genus Enterococcus faecalis Enterococcus faecium Environment Epithelial Cells Equipment Escherichia coli Fellowship Food Gene Expression General Hospitals Genes Genetic Genetic Epistasis Genetic Processes Goals Grant Health Human Hyperthermia Hypoxia Immune Immune response Immune system Infection Inflammation Inflammatory Intestines Invertebrates Laboratories Liquid substance Malignant Neoplasms Mammals Manuscripts Massachusetts Mediating Mentors Methods Microbe Molecular Morbidity - disease rate Mus Natural Immunity Nematoda Oxidative Stress Pathway interactions Personal Satisfaction Play Positioning Attribute Preparation Probiotics Process Property Pseudomonas Pseudomonas aeruginosa Publications Reporter Reporting Resistance Role Scientist Signal Transduction Source Specificity Stress Symptoms Testing Therapeutic Training Vancomycin Resistance Vertebrates adaptive immunity antimicrobial base biological adaptation to stress career chemical genetics immune activation insight interest killings knock-down macrophage medical schools microbial microbiome mitogen-activated protein kinase p38 mortality novel pathogen prevent protective effect response skills small molecule

项目摘要

DESCRIPTION (provided by applicant): The spread of antimicrobial resistance is quickly outstripping the development of novel antibiotics, creating a looming danger for human health and well-being. One means for avoiding this health crisis is the identification of mechanisms to stimulate the innate immune system of the host instead, enabling increased microbial clearance. In addition, host stimulation is likely to prove a more difficult target for the adaptive genetic processes of microbes, as it unbalances the host-pathogen interaction, rather than simply killing the pathogen or preventing its replication. For this grant, I will utilize a novel C. elegans liqui infection assay that I have developed and characterized. C. elegans possesses evolutionarily conserved innate immune pathways similar to those of humans. In Specific Aim 1, the mechanisms used by small molecules with immunostimulatory properties identified in my earlier efforts will be characterized. I will also determine whether this activity is conserved by testing or activation and polarization of murine macrophages. In this fashion, insights into mechanisms of immune activation in vertebrate model organisms will be gained, potentially identifying novel targets for human therapeutics. For Specific Aim 2, I will investigate a mechanism of immune stimulation induced by rearing worms on a specific bacterial food source. The stimulatory mechanisms uncovered may yield new insights into intestinal infections, autoimmune disorders, and intestinal inflammatory conditions. Portions of each aim will be undertaken while I complete my mentored postdoctoral fellowship, but both will be completed once I have an independent position. My current environment, at both the institutional and the laboratory levels, is outstanding. Dr. Fred Ausubel, one of my mentors, pioneered the study of C. elegans innate immunity. Dr. Ruvkun is a leader in the field of stress responses in C. elegans. I've had the opportunity to be co-mentored by both of these exemplary scientists, maximizing my training. In addition, the facilities, equipment, and scientific environment at Massachusetts General Hospital and Harvard Medical School, where I am jointly appointed, are amongst the best in the world. I am interested in developing increased understanding about the integrated the responses to abiotic (e.g., hyperthermia, hypoxia, oxidative stress) and biological stresses (including infection, inflammation, and cancer). Toward that end, my career has focused on assembling the skills necessary to probe these pathways. My immediate career plans include publication of ongoing analysis regarding the host aspect of the liquid killing assay that I have developed. This will more solidly ground the findings that will be acquired during this grant. The next important step in that progression involves a transition to an independent position and acquiring preliminary data for an R01 grant application, which will be greatly facilitated by the acquisition of this grant.

描述（由申请人提供）：抗菌素耐药性的蔓延速度很快超过了新型抗生素的发展速度，对人类健康和福祉造成了迫在眉睫的危险。避免这种健康危机的一种方法是确定刺激宿主先天免疫系统的机制，从而增加微生物清除率。此外，宿主刺激可能被证明是微生物适应性遗传过程的更困难的目标，因为它不平衡宿主与病原体的相互作用，而不是简单地杀死病原体或阻止其复制。对于这笔资助，我将利用我开发和表征的新型线虫液体感染测定法。线虫拥有与人类相似的进化保守的先天免疫途径。在具体目标 1 中，将描述我在早期工作中发现的具有免疫刺激特性的小分子所使用的机制。我还将通过测试或小鼠巨噬细胞的激活和极化来确定这种活性是否保守。通过这种方式，我们将深入了解脊椎动物模型生物体的免疫激活机制，从而有可能确定人类治疗的新靶点。对于具体目标 2，我将研究在特定细菌食物源上饲养蠕虫所诱导的免疫刺激机制。所揭示的刺激机制可能会给肠道感染、自身免疫性疾病和肠道炎症带来新的见解。每个目标的部分内容将在我完成指导的博士后奖学金期间实现，但一旦我拥有独立职位，这两个目标都将完成。我目前的环境，无论是机构还是实验室层面，都是非常出色的。 Fred Ausubel 博士是我的导师之一，他开创了线虫先天免疫研究的先河。 Ruvkun 博士是线虫应激反应领域的领导者。我有机会得到这两位模范科学家的共同指导，最大限度地提高了我的训练水平。此外，我所任职的麻省总医院和哈佛医学院的设施、设备和科研环境都是世界上最好的。我感兴趣的是加深对非生物（例如高温、缺氧、氧化应激）和生物应激（包括感染、炎症和癌症）的综合反应的理解。为此，我的职业生涯专注于整合探索这些途径所需的技能。我近期的职业计划包括发表有关我开发的液体杀灭测定的宿主方面的持续分析。这将为本次拨款期间获得的发现提供更坚实的基础。该进展的下一个重要步骤涉及过渡到独立职位并获取 R01 拨款申请的初步数据，这将通过收购极大地促进这笔补助金。