NLRP10 Inflamasome in Gram-positive Sepsis

革兰氏阳性脓毒症中的 NLRP10 炎性体

基本信息

批准号：
10680214
负责人：
John Le
金额：
$ 4.21万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680214
关键词：
Ablation Adult Alveolar Alveolar Macrophages Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Binding CXC Chemokines Candida albicans Cause of Death Cell physiology Cells Chemotaxis Child Clinical Trials Cytokinesis Data Development Drug usage Epithelial Cells Faculty Failure Family Foundations Functional disorder Goals Gram-Positive Bacteria Health Expenditures High Prevalence Host Defense Human Immune response Immunocompetent Immunologic Receptors Immunotherapy In Vitro Infection Inflammasome Inflammation Innate Immune Response Invaded Knock-out Knockout Mice Knowledge Leucine Leucine-Rich Repeat Leukocytes Ligands Lower Respiratory Tract Infection Lung Lung infections Macrophage Mediating Mediator Membrane Mentors Methods Morbidity - disease rate Mus Myelogenous Myeloid Cells National Research Service Awards Natural Immunity Neutrophil Infiltration Organ Organ failure Pathogenesis Pathologic Phagocytosis Play Pneumonia Population Positioning Attribute Predisposition Production Proteins Public Health Reporting Research Training Respiratory Tract Infections Role Sepsis Septicemia Spleen Staphylococcus aureus infection Stromal Cells System Testing Tissues Toll-like receptors Up-Regulation Vaccines common treatment experience experimental study extracellular human pathogen immunosuppressed in vivo innate immune mechanisms insight marenostrin methicillin resistant Staphylococcus aureus mortality mouse model neutrophil novel therapeutic intervention novel therapeutics pathogen pressure receptor recruit response sensor septic tissue injury

项目摘要

ABSTRACT Sepsis is an important cause of mortality, morbidity, and health care expenditures in immunocompetent and immunosuppressed populations globally. Sepsis can lead to tissue injury, and eventually results in tissue dysfunction and subsequent failure. Lower respiratory tract infections are a prominent inducer of septicemia/sepsis (aka pneumonia-derived sepsis). Antibiotics are common treatments for these infections. However, the use of these drugs will apply pressure on the bacterium to gain antibiotic resistance. Therefore, there is a strong need for to broaden our knowledge and the development of new methods of treatment. In this regard, vigorous recruitment of neutrophils to clear bacteria is a key innate immune mechanism. Paradoxically, uncontrolled neutrophil leads to extensive tissue damage and organ failure. In addition to membrane bound Toll-Like Receptors (TLRs), cytosolic NOD-like receptors (NLRs) serve as critical molecules of innate immunity in pathological settings. Selective NLRs termed “Inflammasomes” which are key receptors and/or sensors in innate immunity that induce inflammation in response to invading pathogens. Among inflammasomes, NLR family pyrin domain containing 3 (NLRP3) is the most studied and has been shown to play an important role during bacterial respiratory infections. However, the role of NACHT, leucine-rich repeat (LRR), and PYD containing protein 10 (NLRP10) in Gram-positive pneumonia remains to be delineated because this is a recently identified inflammasome and does not have a leucine rich domain (LRR). Our lab preliminary data demonstrated that (1) pneumonic human lungs show upregulated NLRP10 expression in macrophages, neutrophils, and epithelial cells; (2) mouse lungs display upregulation of NLRP10 in myeloid and structural cells following sepsis; and (3) NLRP10 knockout (KO) mice show reduced bacterial burden in the lungs and decreased bacterial dissemination to extrapulmonary organs following Gram-positive infection. Taken together, this preliminary data led to the hypothesis that the NLRP10 inflammasome is a central regulator of organ damage in Gram-positive pneumonia-induced sepsis. Two related but independent aims have been proposed: (1) To delineate the mechanisms by which NLRP10 inflammasome regulates pathogen clearance during Gram-positive infection; and (2) To determine if ablation of NLRP10 inflammasome can modulate alveolar macrophage, neutrophil, and alveolar type II epithelial cell function in Gram-positive infection. The proposed studies will uncover mechanistic insights into the role of NLRP10 on pneumonia- induced sepsis. The National Research Service Award will enable the PI to gain mentored research training from a more experienced faculty along with an outstanding dissertation committee in order to obtain an academic position.

抽象的脓毒症是免疫功能正常者死亡、发病和医疗保健支出的重要原因全球范围内的免疫抑制人群可能会导致组织损伤，并最终导致组织功能障碍和随后的衰竭是主要的诱因。败血症/败血症（又称肺炎源性败血症）是这些疾病的常见治疗方法。然而，这些药物的使用会给细菌施加压力以获得抗生素。因此，我们迫切需要拓宽我们的知识并开发新的知识。在这方面，积极招募中性粒细胞来清除细菌是一个关键的先天性治疗方法。矛盾的是，不受控制的中性粒细胞会导致广泛的组织和器官损伤。除了膜结合型 Toll 样受体 (TLR) 外，还有胞质 NOD 样受体 (NLR)。作为病理环境中先天免疫的关键分子，称为选择性 NLR。 “炎症小体”是先天免疫中的关键受体和/或传感器，可诱导炎症对入侵病原体的反应在炎症体中，NLR家族pyrin结构域包含3（NLRP3）。是研究最多的，并已被证明在细菌性呼吸道感染过程中发挥重要作用。然而，NACHT、富含亮氨酸重复序列 (LRR) 和含有蛋白 10 (NLRP10) 的 PYD 在革兰氏阳性肺炎仍有待描述，因为这是最近发现的炎症小体并且不具有富含亮氨酸的结构域 (LRR) 我们实验室的初步数据表明 (1)。人类肺炎患者的巨噬细胞、中性粒细胞和中性粒细胞中 NLRP10 表达上调上皮细胞；(2) 小鼠肺在骨髓细胞和结构细胞中表现出 NLRP10 的上调 (3) NLRP10 敲除 (KO) 小鼠显示肺部细菌负荷减少，并减少革兰氏阳性感染后细菌传播到肺外器官。初步数据得出这样的假设：NLRP10 炎症小体是器官的中央调节因子革兰氏阳性肺炎引起的败血症有两个相关但独立的目标。提出：（1）描绘NLRP10炎症小体调节病原体的机制革兰氏阳性感染期间的清除；以及（2）确定 NLRP10 炎性体的消融是否可以调节革兰氏阳性细胞的肺泡巨噬细胞、中性粒细胞和肺泡 II 型上皮细胞功能拟议的研究将揭示 NLRP10 对肺炎作用的机制。国家研究服务奖将使 PI 能够获得指导性研究。来自经验丰富的教师和优秀论文委员会的培训，以便获得学术职位。