Characterization of Neutrophil Decision making during Swarming to Fungal Pathogens

中性粒细胞聚集到真菌病原体过程中决策的特征

• 批准号: 10444144
• 负责人: Alex Hopke
• 金额: $ 16.08万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444144
• 关键词: Address; Antifungal Agents; Antifungal Therapy; Automobile Driving; Behavior; Biological Assay; Biology; CSF3 gene; Candida albicans; Cells; Chemicals; Complex; Containment; Data; Decision Making; Development; Devices; Elements; Ensure; Event; Faculty; Foundations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Host Defense; Human; Hyphae; Immune; Immune system; Immunity; Individual; Infection; Inflammation; Investigation; Knowledge; Mediating; Mediator; Mentors; Microbial Biofilms; Mission; Modernization; Molecular; Molecular Analysis; Molecular Probes; Morbidity - disease rate; Morphology; Mycoses; National Institute of Allergy and Infectious Disease; Natural Immunity; Pathway interactions; Patients; Pattern; Phase; Positioning Attribute; Public Health; Publishing; Receptor Cell; Research; Risk; Role; Scientist; Signal Pathway; Signal Transduction; Therapeutic; Visual; Work; career; combat; cytokine; design; fighting; fungus; improved; infection risk; inhibitor; microorganism; mortality; neutrophil; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic fungus; pathogenic microbe; patient population; programs; receptor; recruit; research faculty; response; skills; targeted treatment; tenure track; therapeutic development; therapeutic target; tool

Project Summary Invasive fungal infections are a serious public health threat and are associated with high mortality rates, demonstrating that current antifungal therapies are inadequate. While innate immunity is known to be critical for host defense against fungi, these complex host-pathogen interactions remain poorly elucidated. Recently, a novel behavior of neutrophils, a key innate immune cell for antifungal defense, has been characterized, that of neutrophil swarming. Swarming is thought to play a role in the containment of pathogenic microbes, but its role in antifungal defense is poorly characterized, representing a significant gap in knowledge in neutrophil function. The hypothesis driving this research application is that the early events in swarming are critical determinants of if the pathogen will be successfully contained and that characterization of these pathways will highlight novel therapeutic options for optimizing neutrophil function during infection and inflammation. Unfortunately, detailed study of these host-pathogen swarming interactions has been hindered by the shortcomings of current experimental assays. To address this, we have developed and optimized a novel microscale device to allow us to characterize human neutrophil swarming to live fungal pathogens. This microspotting assay allows us to pattern live microorganisms in large arrays, with direct access both visually and to supernatants for molecular analysis. The objective of this application is therefore to leverage novel microscale tools to allow rigorous investigation of the dynamic interactions between host immunity and live fungi during swarming to expand our understanding of swarming biology. We will do this by via the pursuit of two specific aims (1) Identify the molecular mechanisms by which neutrophils decide to initiate swarming behavior and (2) Elucidate the molecular pathways that enhance swarming mediated fungal killing. In the short term, this research is expected to generate critical knowledge on the role of neutrophil swarming in antifungal defense. Leveraging these tools and the knowledge they generate, the long term goal is the development of improved and novel therapeutic options for patients with invasive fungal infections. The work will also provide a strong foundation which the candidate can use to achieve his immediate career goals of attaining an independent, tenure-track faculty position and to progress towards his long term career goals of a tenured research faculty position with a unique academic research program studying innate host- pathogen interactions during fungal infection. In order to attain these career goals, the candidate will also assemble an effective mentoring and consulting team to promote the successful completion of research and the continuing improvement of grantsmanship and lab management skills. These career goals and the proposed research are therefore fulfil NIAID’s mission to pursue and identify novel therapeutic strategies to combat infection and to support the transition of junior scientists into independent faculty positions via the K22.

项目概要 侵袭性真菌感染是严重的公共卫生威胁，并与高死亡率相关， 表明目前的抗真菌疗法是不够的。虽然已知先天免疫至关重要 对于宿主对真菌的防御，这些复杂的宿主-病原体相互作用仍然知之甚少。最近，一个 中性粒细胞（抗真菌防御的关键先天免疫细胞）的新行为已被表征， 中性粒细胞聚集。蜂群被认为在遏制病原微生物方面发挥了作用，但其作用 抗真菌防御的特征尚不清楚，代表中性粒细胞知识的重大差距 功能。推动这项研究应用的假设是蜂群的早期事件至关重要 病原体能否被成功遏制的决定因素以及这些途径的特征 重点介绍在感染和炎症期间优化中性粒细胞功能的新治疗方案。 不幸的是，对这些宿主-病原体集群相互作用的详细研究受到了阻碍 当前实验分析的缺点。为了解决这个问题，我们开发并优化了一种新颖的 微型装置使我们能够表征人类中性粒细胞聚集到活真菌病原体的情况。这 微点分析使我们能够在大型阵列中对活微生物进行模式化，并可以通过视觉直接访问 并将上清液用于分子分析。因此，该应用程序的目标是利用新颖的 微型工具可以严格研究宿主免疫和活体之间的动态相互作用 集群期间的真菌，以扩大我们对集群生物学的理解。我们将通过追求来做到这一点 两个具体目标 (1) 确定中性粒细胞决定启动集群的分子机制 (2) 阐明增强群体介导的真菌杀灭的分子途径。简而言之 从长远来看，这项研究预计将产生关于中性粒细胞群在抗真菌药物中的作用的关键知识 防御。利用这些工具及其产生的知识，长期目标是开发 为侵袭性真菌感染患者提供改进和新颖的治疗选择。 这项工作还将为候选人可以用来实现他的直接职业生涯提供坚实的基础 获得独立的终身教授职位并朝着长期职业发展的目标 终身研究教员职位的目标，具有独特的学术研究计划，研究先天宿主- 真菌感染期间病原体的相互作用。为了实现这些职业目标，候选人还将 组建一支有效的指导和咨询团队，促进研究和成果的成功完成 资助能力和实验室管理技能的持续改进。这些职业目标和 因此，拟议的研究将履行 NIAID 的使命，即追求和确定新的治疗策略，以 对抗感染并支持初级科学家通过 K22 过渡到独立教职职位。