Functional Microbiomics, Inflammation and Pathogenicity

功能微生物组学、炎症和致病性

• 批准号: 10852188
• 负责人: Richard J Lamont
• 金额: $ 65.38万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852188
• 关键词: Acute; Affinity; Asthma; Bacterial Infections; Binding; Biology; Cells; Cementation; Centers of Research Excellence; Cessation of life; Chemotactic Factors; Chemotaxis; Chronic; Collaborations; Core Facility; Cytometry; Data; Development; Disease; Environment; Exposure to; Fibrosis; Flow Cytometry; Funding; Future; Generations; Goals; Gout; Grant; Image; Immune; Immune Evasion; Immune response; Immunologist; Infection; Infection Control; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inhalation; Kentucky; Knowledge; LTB4R gene; Laboratories; Leukocytes; Leukotriene B4; Lipids; Location; Lung; Mediating; Molecular; Mycoses; National Institute of General Medical Sciences; Nature; Parasitic infection; Pathogenesis; Pathogenicity; Pathway interactions; Plague; Pneumonic Plague; Population; Process; Production; Pulmonary Inflammation; Regulation; Resolution; Resources; Role; Sentinel; Signal Pathway; Signal Transduction; Silicon Dioxide; Silicosis; Site; Spatial Distribution; Sterility; Technology; Therapeutic Intervention; Time; Tissues; Universities; Yersinia pestis; cancer immunotherapy; chronic inflammatory disease; defined contribution; immune modulating agents; improved; inflammatory milieu; innovative technologies; interest; lipid mediator; microbiome research; mouse model; multiplexed imaging; pathogen; programs; receptor; recruit; response; single-cell RNA sequencing; tool; transcriptome sequencing; transcriptomics; tumor immunology

ABSTRACT Inflammation is essential to protect us against infection. To contain the infection, leukocytes must rapidly sense pathogens and recruit additional immune cells to infected tissues. However, once the infection is contained, inflammation must also be quickly resolved to avoid collateral tissue damage caused by activated immune cells. Therefore, initiation and resolution of inflammation are tightly regulated processes. Lipid mediators of inflammation are essential for both the initiation and resolution of inflammation. Leukotriene B4 (LTB4) is a pro- inflammatory lipid rapidly produced in response to infection. LTB4 binding to the BLT1 receptor recruits and activates resident and circulating leukocytes to sites of infection, and LTB4/BLT1 signaling is required to effectively control infections. However, persistent LTB4 synthesis can also lead to chronic inflammation and tissue damage associated with inflammatory diseases such as gout, asthma, and silicosis. Because dysregulation of LTB4 impacts both acute and chronic inflammation, defining the specific contribution of this potent chemoattractant to the regulation of inflammation is essential to understanding the molecular mechanisms of inflammatory initiation and resolution. We have demonstrated that dysregulation of LTB4-mediated inflammation occurs during both silica-induced sterile inflammation (i.e., persistent LTB4 production) and Yersinia pestis infection (i.e., inhibited LTB4 production). While we have established a role for this signaling pathway in both diseases, the precise nature of this dysregulation and its impact on inflammatory cell programming remains a critical gap in our knowledge pertaining to LTB4 regulation of inflammatory responses. Therefore, the goal of this project is to use the Core Resource Centers at the University of Louisville's COBREs and the Kentucky INBRE to define the temporal and spatial regulation of inflammation during LTB4 dysregulation induced by silica inhalation or Y. pestis infection. We will achieve this through the application of cutting-edge technologies including single cell RNA sequencing and imaging mass cytometry. Defining these mechanisms of regulation is key to understanding how inflammation is properly controlled and can reveal potential therapeutic interventions to better treat infection and diseases resulting from chronic inflammation.

摘要 炎症对于保护我们免受感染至关重要。为了控制感染，白细胞必须迅速感知 病原体和招募额外的免疫细胞感染的组织。不过，一旦感染得到控制， 炎症也必须迅速解决，以避免由激活的免疫细胞引起的附带组织损伤。 因此，炎症的起始和消退是严格调控的过程。脂质介质 炎症对于炎症的引发和消退都是必不可少的。白三烯B4（LTB 4）是一种前 炎症脂质响应于感染而迅速产生。LTB 4与BLT 1受体结合募集， 激活驻留和循环白细胞到感染部位，需要LTB 4/BLT 1信号传导， 有效控制感染。然而，持续的LTB 4合成也可导致慢性炎症， 与炎性疾病如痛风、哮喘和硅肺有关的组织损伤。因为 LTB 4的调节异常影响急性和慢性炎症，定义了这种调节的具体贡献。 一种有效的趋化因子对炎症的调节是理解其分子机制的关键 炎症的发生和消退我们已经证明，LTB 4介导的调节异常 炎症在二氧化硅诱导的无菌炎症（即，持续LTB 4生产）和耶尔森氏菌 鼠疫感染（即，抑制LTB 4产生）。虽然我们已经确定了这种信号通路在 这两种疾病，这种失调的确切性质及其对炎症细胞编程的影响仍然存在， 这是我们对LTB 4调节炎症反应的认识中的一个关键空白。因此，目标 该项目将利用路易斯维尔大学的COBREs和肯塔基州的核心资源中心 INBRE用于定义二氧化硅诱导的LTB 4失调期间炎症的时间和空间调节 吸入或Y.鼠疫感染我们将通过应用尖端技术来实现这一目标 包括单细胞RNA测序和成像质谱细胞术。定义这些调节机制是 了解炎症如何得到适当控制并揭示潜在治疗干预措施的关键 以更好地治疗感染和由慢性炎症引起的疾病。