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.

项目概要肺炎是全球死亡的主要原因，影响全球约 4.5 亿人每年，并导致约 400 万人死亡。尽管需要针对开发新抗生素迫在眉睫，需要研究和更好地了解宿主免疫反应从未如此伟大。我们之前的研究鉴定并表征了动物含血红素过氧化物酶的新成员 (hPx) 家族，血管过氧化物酶 1 (VPO1)。与 hPx 家族的其他成员一样，VPO1 产生次卤酸，能够杀死细菌。我们的数据显示，VPO1 缺陷小鼠的肺炎中的生存。除了其催化结构域外，VPO1 还具有一个独特的 N 末端，其中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，与脂多糖高度特异性结合 (LPS)，并杀死革兰氏阴性菌。此外，我们的数据表明 LPS 会导致更强的炎症 VPO1 缺陷小鼠的反应； VPO1 可以抑制 LPS 介导的 Toll 样受体 4 的激活。结果引出了我们的中心假设，即 VPO1 在先天免疫中具有双功能作用，既通过杀菌作用 LPS 介导的炎症反应的活性和抑制。在强有力的初步数据的指导下，我们提出追求三个具体目标：（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) 评估外源性递送 VPO1 是否可以恢复 VPO1 缺陷小鼠的宿主防御功能。总的来说，我们提出的研究将通过确定和描述新的特征来广泛影响该领域宿主防御酶 VPO1，具有杀死细菌和减少 LPS 刺激的双重功能炎。这些研究将揭示宿主与病原体相互作用的新分子机制可能提供一种新的（超越抗生素）免疫调节治疗肺炎的治疗策略和内毒素感染性休克。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peroxidasin contributes to lung host defense by direct binding and killing of gram-negative bacteria.

过氧化酶通过直接结合和杀死革兰氏阴性菌来促进肺宿主防御。

DOI：
发表时间：
2018
期刊：
影响因子：
6.7
作者：
Shi, Ruizheng;Cao, Zehong;Li, Hong;Graw, Jochen;Zhang, Guogang;Thannickal, Victor J;Cheng, Guangjie
通讯作者：
Cheng, Guangjie

Recombinant Myeloperoxidase as a New Class of Antimicrobial Agents.

重组髓过氧化物酶作为一类新型抗菌剂。