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Genetic and Pharmacologic Evaluation of the Role of HIF-1a in asthma

HIF-1a 在哮喘中作用的遗传学和药理学评价

基本信息

批准号：
8305975
负责人：
Laura Elise Crotty Alexander
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305975
关键词：
Accident and Emergency department Acute Adult Affect Airway Resistance Allergens Allergic Allergic inflammation American Animal Experiments Antigen Presentation Antigens Asthma Bone Marrow Cells Chronic Complex Cytoplasmic Granules Data Dendritic Cells Development Disease Effector Cell Evaluation Extrinsic asthma Family Genes Genetic Goals Goblet Cells HIF1A gene Half-Life Healthcare Histamine Hospitalization Hyperplasia Hypersensitivity Hypertrophy Hypoxia Inducible Factor IgE Immunosuppressive Agents In Vitro Incidence Infection Inflammation Inflammatory Inflammatory Response Interleukin-13 Interleukin-4 Laboratories Lead Leukocytes Literature Lung Lupus Lymphocyte Mammalian Cell Mediating Medical Mentors Migration Assay Military Personnel Modeling Molecular Mucous body substance Mus Myelogenous NF-kappa B Navy Personnel Ovalbumin Pathogenesis Pathway interactions Peptides Phagocytosis Pharmaceutical Preparations Phenotype Phosphotransferases Play Population Predisposition Process Production Proteins Reagent Research Rheumatoid Arthritis Role Secondary to Series Serum Signal Transduction Smooth Muscle Stimulus Structure of parenchyma of lung System Testing Therapeutic Time Tissues Veterans Visit Western Blotting Work YC-1 airway inflammation airway obstruction airway remodeling allergic response antigen challenge asthmatic patient cytokine cytotoxic design disorder control eosinophil experience extracellular genetic manipulation health care quality human MAPK14 protein hypoxia inducible factor 1 in vivo inhibitor/antagonist intraperitoneal lipid mediator macrophage mast cell member migration neutrophil prevent research study response small molecule transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): Asthma is an extremely common disease, affecting 6.4% of American adults over the course of their lives1. Determining the molecular mechanisms behind the development and progression of asthma will lead to new treatment targets, more specific treatment options, and better control of the disease. Asthma is an inflammatory disease characterized by hypertrophy of smooth muscle, airway obstruction, and increased mucous production3. Dendritic cells, eosinophils, and mast cells are known to play a role in the development and progression of asthma, however the molecular mechanisms behind the disease have not been elucidated. Hypoxia inducible factor-11 (HIF-11) is a transcription factor recently identified as a master regulator of the inflammatory capacity of myeloid cells4; 5. HIF-11 mediates many critical functions of macrophages and neutrophils in inflammation4; 6. Because it is found in all mammalian cells, regulates over 100 functional genes, and modulates NF-:B pathways that are known to be up regulated during allergic inflammation7; 8, I hypothesize that HIF-11 regulates allergic inflammation in asthma. The pathogenesis underlying the development of asthma can be broken down into two components. First, an allergic response to a specific allergen is initiated. Second, airway inflammation develops in response to allergen re-exposure. The goal of the work proposed here is to explore how the transcription factor Hypoxia Inducible Factor-11 (HIF-11) modulates the pathogenesis of asthma, and to probe mechanistically the molecular pathways through which HIF-11 acts in this capacity. I hypothesize that (a) Hypoxia Inducible Factor-11 is a critical regulator of molecular pathways involved in allergic inflammation; (b) HIF-11 in dendritic cells plays a significant role in the initiation of the allergic airway response; and (c) HIF-11 in eosinophils plays a role in the perpetuation and progression of airway inflammation. I will explore how genetic manipulation of HIF-11 levels in leukocytes influences asthma susceptibility, and examine whether a therapeutic strategy to pharmacologically inhibit HIF-11 can be effective in reducing airway inflammation and reactivity. We will utilize an ovalbumin (OVA) model of allergic inflammatory airways disease in mice. Mice will be evaluated for the magnitude of allergic response via IgE, histamine, IL-4, and IL-13 levels, airway resistance, inflammatory pulmonary infiltrates, and airway remodeling. Detailed, mechanistic studies of eosinophils and dendritic cells will be done in vitro, with cells derived from mouse bone marrow. These studies will utilize migration assays, FACS analysis, ELISAs, Western blots, and real-time quantitative PCR. In this proposal, I will determine whether HIF-11 initiates or sustains allergic inflammatory airway disease development in mice. Specifically, these studies will rigorously test whether HIF-11 regulates dendritic cells and eosinophil function in allergic inflammation leading to asthma. Unique mouse genetic reagents, in which HIF-11 levels have been markedly reduced or constitutively increased in leukocyte lineages, are available for me to definitively test these hypotheses in a detailed, mechanistic fashion in vivo and ex vivo. Beyond these powerful genetic approaches, I propose a parallel series of pharmacologic experiments utilizing small molecule inhibitors to globally suppress HIF-11. I hypothesize that because HIF-11 is regulated at the protein level with a half-life of seconds9, anti-HIF-11 immunosuppressant agents will lead to a rapid decrease in inflammation in a manner that is rapidly reversible upon discontinuation of the agent. Therefore, if severe asthmatic patients were treated chronically with a HIF-11 inhibitor and developed an infection, the HIF-11 antagonist could be temporarily stopped to provide a rapid return of normal leukocyte function. As well as other chronic inflammatory diseases (rheumatoid arthritis, lupus, etc.), I hypothesize that HIF-11 inhibition may offer an exciting strategy for the management of asthma.

描述（由申请人提供）：