The Roles of LPS-Binding Protein Vascular Peroxidase-1 in Innate Immunity

LPS 结合蛋白血管过氧化物酶 1 在先天免疫中的作用

基本信息

批准号：
10320902
负责人：
Guangjie Cheng
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-04 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320902
关键词：
2 year old Acids Acute Pneumonia Address Adenoviruses Affect Age-Years Animals Antibiotics Bacteria Binding Blood Circulation Blood Vessels Cardiovascular system Catalytic Domain Cause of Death Cells Cessation of life Child Competitive Binding Data Development Drug or chemical Tissue Distribution Effectiveness Endotoxins Enzymes Epithelial Escherichia coli Family Future Generations Goals Gram-Negative Bacteria Heme Host Defense Human Hydrogen Peroxide Immune response Immunoglobulin Domain Immunotherapy In Vitro Infectious Agent Inflammation Inflammatory Response Knowledge Lead Leucine-Rich Repeat Lipopolysaccharides Liquid substance Lung Mediating Mediator of activation protein Modeling Molecular Mus N-terminal Natural Immunity Outcome Pattern Recognition Peroxidases Persons Play Pneumonia Pseudomonas aeruginosa Pulmonary alveolar structure Recombinants Regulation Research Respiratory Tract Infections Role Septic Shock Signal Transduction Specificity TLR4 gene Therapeutic Validation Wild Type Mouse antimicrobial drug bactericide base clinical development human subject immunoregulation in vitro activity in vivo lipopolysaccharide-binding protein member mortality multi-drug resistant pathogen novel novel drug class pathogen pneumonia model pneumonia treatment reconstitution young adult

项目摘要

PROJECT SUMMARY Pneumonia is a leading cause of mortality worldwide, affecting approximately 450 million people globally per year, and results in about 4 million deaths annually. Although the need for research directed toward development of new antibiotics is urgent, the need to study and better understand host immune responses has never been greater. Our previous studies identified and characterized a new member of animal heme-containing peroxidase (hPx) family, Vascular peroxidase 1 (VPO1). Like other members of the hPx family, VPO1 generates hypohalous acids and is able to kill bacteria. Our data show that VPO1-deficient mice have decreased survival in pneumonia. In addition to its catalytic domains, VPO1 has a unique N-terminus containing five leucine-rich repeats and four immunoglobulin domains, which bind with high specificity to lipopolysaccharide (LPS), and kill gram-negative bacteria. Furthermore, our data reveal that LPS causes stronger inflammatory responses in VPO1-deficient mice; VPO1 can inhibit LPS-mediated activation of Toll-like receptor 4. These results lead to our central hypothesis that VPO1 has a bifunctional role in innate immunity, both via bactericidal activities and inhibition of LPS-mediated inflammatory responses. Guided by strong preliminary data, we propose to pursue three Specific Aims: (1) define the molecular mechanisms of VPO1-mediated bactericidal activities; (2) evaluate functional roles of VPO1 in regulation of LPS-mediated inflammatory responses; (3) assess whether exogenous delivery of VPO1 restores host defense function in VPO1-deficient mice. Collectively, our proposed research will broadly impact the field by determining and characterizing a new host defense enzyme, VPO1, with dual function in bacterial killing and reduction of LPS-stimulated inflammation. These studies will uncover new molecular mechanisms of host-pathogen interaction and potentially provide a novel (beyond antibiotics) therapeutic strategy of immune-modulation to treat pneumonia and endotoxin septic shock.

项目摘要肺炎是全球死亡率的主要原因，全球约有4.5亿人每年，每年大约造成400万人死亡。尽管需要研究的需要新抗生素的开发是紧迫的，学习和更好地理解宿主免疫反应的需求从来没有更大。我们以前的研究确定并表征了含血红素血红素过氧化物酶的新成员（HPX）家族，血管过氧化物酶1（VPO1）。像HPX家族的其他成员一样，VPO1生成低钙化酸，能够杀死细菌。我们的数据表明，VPO1缺陷小鼠已经减少肺炎的生存。除了其催化域，VPO1还具有独特的N末端，包含五个富含亮氨酸的重复序列和四个免疫球蛋白结构域，它们具有高特异性与脂多糖结合（LPS），并杀死革兰氏阴性细菌。此外，我们的数据表明LP会引起更强的炎症 VPO1缺陷小鼠的反应； VPO1可以抑制LPS介导的Toll样受体的激活4。结果导致我们的中心假设，即VPO1在先天免疫中具有双功能，均通过杀菌性 LPS介导的炎症反应的活性和抑制。在强大的初步数据的指导下，我们提议追求三个特定目的：（1）定义VPO1介导的杀菌的分子机制活动; （2）评估VPO1在调节LPS介导的炎症反应中的功能作用；（3）评估VPO1的外源递送是否恢复VPO1缺陷小鼠中的宿主防御功能。总的来说，我们拟议的研究将通过确定和表征新的研究来广泛影响该领域宿主防御酶，VPO1，在细菌杀死和减少LPS刺激中具有双重功能炎。这些研究将发现宿主 - 病原体相互作用的新分子机制和有可能提供免疫调节的新颖（抗生素）治疗策略，以治疗肺炎和内毒素败血性休克。