RELM Peptides Alter Lung Defense

RELM 肽改变肺部防御能力

基本信息

批准号：
7707279
负责人：
Thomas R Korfhagen
金额：
$ 18.96万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7707279
关键词：
Affect Air Antibodies B-Lymphocytes Bleomycin Breathing C-terminal Cardiovascular Diseases Cell physiology Cells Chronic Clinical Collectins Cysteine Data Defense Mechanisms Defensins Development Effectiveness Effector Cell Endotoxins Epidermal Growth Factor Receptor Epithelial Epithelium Equilibrium Exposure to Goals Haemophilus influenzae Hypoxia Immune Immune response Immune system Immunotherapy In Vitro Individual Infection Inflammation Inflammatory Interleukin-13 Knowledge Laboratories Lactoferrin Lead Lung Mediating Mediator of activation protein Memory Memory B-Lymphocyte Microbe Modeling Molecular Mucous Membrane Muramidase Mus Natural Immunity Nitrogen Outcome Oxygen Pathway interactions Peptides Phagocytosis Play Production Property Pseudomonas Pseudomonas aeruginosa Research Project Grants Respiratory syncytial virus Risk Role Sentinel Signal Pathway Signal Transduction Sterility Stimulus Streptococcus Group B Surface T-Lymphocyte Testing Transgenic Mice Transgenic Organisms Vaccine Design Viral antigen challenge base cytokine in vivo inhibitor/antagonist insight killings macrophage microbial mouse model mucosal vaccination mucosal vaccine neutrophil novel pathogen prevent research study resistin respiratory response vaccine development vaccine effectiveness

项目摘要

DESCRIPTION (provided by applicant): The RFA, Immune Defense Mechanisms at the Mucosa, requests exploratory/developmental research projects that propose to study immune mechanisms at respiratory mucosal surfaces to gain new insights that will facilitate vaccine development to protect mucosal surfaces from infection and inflammation. Antibody producing and memory B cells and T cells populate the lung indicating a capacity to form adaptive immune responses, yet development of respiratory mucosal vaccines has been difficult. A successful mucosal vaccine needs to provide for memory, subsequent recognition, and clearance of pathogens. The lower pulmonary mucosa generally remains sterile in spite of continuous exposure to inhaled microbes. Lung mucosal protection is attributable to the innate and adaptive immune system, cells and molecules, which enhance microbial clearance. There is little knowledge of mucosal properties that lead to reduced microbial clearance. We have identified a property of the mucosal surface that reduces microbial clearance, which could compromise the effectiveness of mucosal vaccines. Resistin-like molecules (RELM peptides) are induced at the mucosal surface by inflammatory stimuli. Using a transgenic mouse model of inducible RELM-? produced in the pulmonary epithelium, we have identified a novel property of RELM-?, which is to cause reduced bacterial clearance from the lung in vivo. These data suggest that antigen challenges may induce RELM peptides leading to reduced microbial clearance. The purpose of this application is gain knowledge of this paradoxical immune response by testing the central hypothesis that RELM peptides prevent efficient elimination of pathogens by inhibiting innate clearance mechanisms. To test this hypothesis we will use RELM-? as a model and (1) determine whether RELM-? affects clearance of pathogens which are targets of mucosal vaccines (Aim 1); (2) determine if RELM-? affects sentinel cells and reduces levels of known innate molecules (Aim 2); (3) determine if levels of RELM-? or RELM-? signaling can be reduced using clinically applicable pharmacological inhibitors (Aim 3). The long-term goal is to gain knowledge of mucosal properties that cause reduced clearance, which ultimately may compromise effectiveness of vaccines. RELEVANCE: Individuals with underlying chronic lung or cardiovascular diseases have increased risk of inhaled pathogens escaping lung protective mechanisms causing lung infections and these groups of individuals could benefit from the development of mucosal vaccines against likely lung pathogens. The outcome of the interaction between host and pathogen depends on the balance between mechanisms that enhance microbial killing and those that inhibit clearance. We are seeking to gain knowledge regarding how lung RELM molecules reduce microbial clearance.

描述（由申请人提供）：粘膜的RFA，免疫防御机制要求探索性/发育研究项目，该项目建议研究呼吸粘膜表面上的免疫机制，以获得新的见解，以促进疫苗发育，以促进粘膜表面保护粘膜表面免受感染和炎症的保护。产生抗体和记忆B细胞和T细胞填充肺部，表明形成适应性免疫反应的能力，但呼吸粘膜疫苗的发展很困难。成功的粘膜疫苗需要提供记忆，随后的识别和病原体的清除。尽管连续暴露于吸入的微生物，但较低的肺粘膜通常仍然无菌。肺粘膜保护归因于先天和适应性免疫系统，细胞和分子，从而增强微生物清除率。对粘膜特性的了解很少，从而导致微生物清除率降低。我们已经确定了粘膜表面的特性，可降低微生物清除率，这可能损害粘膜疫苗的有效性。通过炎症刺激在粘膜表面诱导抗素样分子（RERM肽）。使用诱导relm-的转基因小鼠模型？在肺上皮产生的，我们已经确定了一个新型的relm？，它会导致体内肺的细菌清除率降低。这些数据表明，抗原挑战可能引起RERM肽，从而导致微生物清除率降低。该应用的目的是通过检验中心假设来了解这种矛盾的免疫反应，即RELM肽通过抑制先天清除机制来防止有效消除病原体。为了检验这一假设，我们将使用relm-？作为模型，（1）确定是否relm-？影响是粘膜疫苗靶标的病原体的清除（AIM 1）；（2）确定是否relm-？影响前哨细胞并降低已知的先天分子的水平（AIM 2）；（3）确定Relm-是否水平？还是relm-？使用临床适用的药理抑制剂可以减少信号（AIM 3）。长期的目标是获取导致清除率降低的粘膜特性的了解，最终可能会损害疫苗的有效性。相关性：具有潜在的慢性肺或心血管疾病的个体增加了吸入病原体的风险，从而逃脱了引起肺部感染的肺部保护机制，而这些个体可能会受益于可能针对可能的肺病原体的粘膜疫苗的发展。宿主与病原体之间相互作用的结果取决于增强微生物杀戮的机制和抑制清除率的机制之间的平衡。我们正在寻求了解如何减少微生物清除率的肺部分子。