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.

项目摘要 侵袭性真菌感染是一个严重的公共健康威胁，并与高死亡率有关， 表明目前的抗真菌疗法是不够的。虽然已知的先天免疫力是至关重要的 对于寄主对真菌的防御，这些复杂的寄主-病原体相互作用仍然很少被阐明。最近，一位 中性粒细胞是抗真菌防御的关键先天免疫细胞，其新的行为已经被表征，即 中性粒细胞蜂拥而至。蜂群被认为在遏制病原微生物方面发挥了作用，但它的作用 在抗真菌防御方面的特点很差，这表明对中性粒细胞的认识存在显著差距。 功能。推动这项研究应用的假设是，蜂群的早期事件是关键的 病原体能否被成功控制的决定因素以及这些途径的特征将 突出在感染和炎症期间优化中性粒细胞功能的新的治疗选择。 不幸的是，对这些宿主-病原体蜂拥相互作用的详细研究受到了 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部小说 微型设备，使我们能够表征人类中性粒细胞蜂拥至活的真菌病原体。这 微斑点分析使我们能够在大阵列中对活微生物进行模式识别，并可在视觉上直接访问 和上清液进行分子分析。因此，该应用程序目标是利用新的 微型工具，可用于严格研究宿主免疫和活体之间的动态相互作用 真菌在成群过程中，扩大了我们对成群生物学的理解。我们将通过以下方式来实现这一点： 两个特定的目标(1)确定中性粒细胞决定启动聚集的分子机制 行为和(2)阐明了增强蜂群介导的真菌杀灭的分子途径。简而言之 学期，这项研究有望产生关于中性粒细胞聚集在抗真菌中的作用的关键知识 防守。利用这些工具和它们产生的知识，长期目标是开发 对侵袭性真菌感染患者的改进和新的治疗选择。 这项工作也将提供一个坚实的基础，候选人可以用来实现他的直接职业生涯 目标是获得一个独立的终身教职职位，并朝着长期的职业生涯迈进 终身研究教师职位的目标是拥有一个独特的研究先天宿主的学术研究计划- 真菌感染过程中病原菌的相互作用。为了实现这些职业目标，应聘者还将 组建一支有效的指导和咨询团队，推动研究和咨询工作的顺利完成 不断提高资质和实验室管理技能。这些职业目标和 因此，拟议研究正在履行NIAID的使命，即寻求和确定新的治疗策略来 与感染作斗争，并支持初级科学家通过K22过渡到独立的教职员工职位。