Molecular Mechanisms of Asthma

哮喘的分子机制

基本信息

批准号：
7204126
负责人：
Julian Solway
金额：
$ 127.7万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2008-08-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7204126
关键词：
A Mouse Absenteeism Absenteeism at work Accounting Acute Address Adult Advisory Committees Affect Age Air Allergens Allergic American Animals Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Apoptosis Apoptotic Asthma Attention Award BTBR Mouse Binding Biological Models Biology Breathing Breeding Bronchoalveolar Lavage Bronchoconstrictor Agents CD28 gene CD4 Positive T Lymphocytes Caring Cataloging Catalogs Cell Cycle Cell Line Cell physiology Cells Characteristics Chicago Child Cholinergic Agents Chronic Chronic Disease Circadian Rhythms Class Classification Clinical Clinical Research Clinical Trials Collaborations Communication Communities Companions Complement Factor B Critical Care Cultured Cells Data Databases Development Discipline Disease Disruption Doctor of Medicine Doctor of Philosophy Doxycycline Eating Effector Cell Elevation Employee Strikes Ensure Epithelial Epithelial Cells Epithelium Equilibrium Ethylnitrosourea Evaluation Exhibits Extrinsic asthma Family Family member Fertility Fibrosis Foundations Functional disorder Funding Future Gene Expression Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genome Genotype Goals Goblet Cells Growth Factor Growth Factor Receptors Histocompatibility Homeostasis Hospitalization Human Human Volunteers Hypersensitivity Hypertrophy IgE ImProv Immune Immune response Immunoglobulin A Immunology Immunotherapy Incidence Individual Induced Mutation Infiltration Inflammation Inflammatory Inflammatory Response Intervention Invasive Investigation JUN gene Joints Lead Learning Life Ligands Ligation Lung Lymphoid MAPK14 gene Maintenance Malignant Neoplasms Maps Measurement Mechanics Mediating Melanocytic nevus Memory Methods Minor Modality Modeling Modification Mole the mammal Molecular Molecular Biology Molecular Genetics Mouse Strains Mus Muscle Cells Mutant Strains Mice Mutation Neurobiology Nitrosourea Compounds Numbers Obstruction Outcome Outpatients Parents Pathologic Pathologic Processes Pathology Pathway interactions Patients Penetrance Performance Personal Satisfaction Pharmaceutical Preparations Phenotype Physicians Physiological Play Point Mutation Population Prevalence Prevention Process Production Productivity Promoter Regions Range Recording of previous events Recruitment Activity Regulation Reporting Research Research Activity Research Infrastructure Research Personnel Research Project Grants Research Training Resistance Resources Role Sampling Schools Scientist Screening procedure Seminal Series Serum Services Severities Side Signal Pathway Signal Transduction Smooth Muscle Myocytes Son Specimen Stimulus Structure Study Subject Sum Surface Surface Antigens Susceptibility Gene Symptoms T-Cell Activation T-Lymphocyte TNFRSF6 gene Tail Techniques Technology Testing Th2 Cells Therapeutic Therapeutic Intervention Thinking Time Tissues Transforming Growth Factors Transgenic Mice Transgenic Model Transplantation Tumor Necrosis Factor-Beta United States United States National Institutes of Health Universities Variant Visit Weaning Yang airway epithelium airway hyperresponsiveness airway inflammation airway remodeling allergic airway disease allergic airway inflammation anti-IgE asthmatic airway atopy base cell type cholinergic cost cost effectiveness crosslink cytokine day eosinophil experience fascinate gene interaction gene therapy genetic analysis genetic linkage analysis genetic pedigree human subject improved in vivo inner city insight interest kindred mast cell mortality mutant novel novel strategies novel therapeutics prevent programs quantum receptor research study respiratory respiratory smooth muscle response stress-activated protein kinase 1 success therapeutic target volunteer

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this AADRC Program is to evaluate the cellular and molecular basis for asthma, in order to identify novel strategies for eventual therapeutic intervention. To achieve this goal, four research projects are proposed to address three interrelated facets of the asthmatic process: immune mechanisms that underlie chronic airway inflammation, apoptotic disruption of airway epithelial integrity, and genetic predispositions to atopy and to airway constrictor hyper-responsiveness. The comprehensive, mechanistic evaluations proposed require special expertise in the fields of immunology, cell signaling, molecular biology, and molecular genetics. An important feature of this AADRC proposal is that scientists from outside the traditional pulmonary community join with senior airways investigators to form a cohesive, interactive research program that incorporates a wide range of new perspectives, technologies, and approaches. Project 1, Role of ICOS Expression Level in Atopy, addresses how genetic variations in the human ICOS gene that have been associated with atopy influence ICOS expression levels, and how these in turn modulate T cell function and allergic airway inflammation. Project 2, Role of Lymphotoxin in IgE Deficiency-induced Airway Inflammation, evaluates how reduced IgE levels in lymphotoxin-deficient mice lead to Th1-dominant airway inflammation and structural changes that mimic chronic severe asthma, and prompts the novel idea that a subset of asthmatics may have Th1-dominant, rather than Th2-dominant, airway inflammation. Project 3, Genetic Basis of Airway Hyper-responsiveness, will identify the mutation(s) and physiological mechanisms that have caused native airway cholinergic hyper-responsiveness in recently established kindred of chemically mutagenized mice. Project 4, Role of TGF-B in Protection Against Airway Epithelial Cell Apoptosis in Asthma, tests the molecular mechanisms by which this growth factor protects normal, but not asthmatic, airway epithelium from apoptosis. These projects form a research program whose sum is greater than its parts, for: (i) they follow a logical thematic progression from basic allergic and non-allergic immune mechanisms in airway inflammation, into epithelial barrier function that constitutes the first line of defense against immune activation, and into identification of gene variations responsible for cardinal features of asthma; (ii) they benefit from considerable exchange of expertise and commonality of approach; and (iii) they take advantage of three common core organizations (Mouse Breeding, Human Subject Recruitment, and Administration) that enhance research efficiency and productivity. Data derived from these collaborative studies will yield new insights into the cellular and molecular mechanisms underlying asthma, and therefore should suggest strategies for novel therapeutic intervention.

描述（由申请人提供）：该AADRC计划的总体目的是评估哮喘的细胞和分子基础，以确定最终治疗干预的新策略。为了实现这一目标，提出了四个研究项目，以解决哮喘过程的三个相互关联的方面：慢性气道炎症，气道上皮完整性的凋亡破坏以及遗传性倾向的免疫机制，以及对ATOPY的遗传倾向和Airway collation缩合。提出的全面的机械评估需要在免疫学，细胞信号传导，分子生物学和分子遗传学领域的特殊专业知识。该AADRC提案的一个重要特征是，来自传统肺部社区之外的科学家与高级航空公司调查人员一起组成了一个有凝聚力的互动研究计划，该计划结合了各种新的观点，技术和方法。项目1（ICOS表达水平在特应性中的作用）解决了与特应性的人类ICOS基因中的遗传变异如何影响ICOS表达水平，以及这些如何调节T细胞功能和过敏性气道炎症。 Project 2, Role of Lymphotoxin in IgE Deficiency-induced Airway Inflammation, evaluates how reduced IgE levels in lymphotoxin-deficient mice lead to Th1-dominant airway inflammation and structural changes that mimic chronic severe asthma, and prompts the novel idea that a subset of asthmatics may have Th1-dominant, rather than Th2-dominant, airway inflammation.项目3（气道高反应性的遗传基础）将确定在最近确定的化学诱变小鼠中引起天然气道胆碱能超反应性的突变和生理机制。项目4，TGF-B在哮喘中防止气道上皮细胞凋亡的保护中的作用，测试了该生长因子保护正常但不能保护哮喘的气道上皮细胞免受凋亡的分子机制。这些项目构成了一个研究计划，其总和大于其部分，因为：（i）它们遵循气道炎症中基本过敏和非过敏性免疫机制的逻辑主题进展，转化为上皮屏障功能，构成了针对免疫激活的第一线，并构成了对基因的识别，是对基因的识别。（ii）他们受益于大量的专业知识和方法的共同点；（iii）他们利用了提高研究效率和生产力的三个共同核心组织（小鼠育种，人类受试者招聘和管理）的优势。从这些协作研究中得出的数据将产生哮喘潜在的细胞和分子机制的新见解，因此应提出新型治疗干预的策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protective effector memory CD4 T cells depend on ICOS for survival.

DOI：
10.1371/journal.pone.0016529
发表时间：
2011-02-18
期刊：
PloS one
影响因子：
3.7
作者：
Moore TV;Clay BS;Ferreira CM;Williams JW;Rogozinska M;Cannon JL;Shilling RA;Marzo AL;Sperling AI
通讯作者：
Sperling AI

Force fluctuation-induced relengthening of acetylcholine-contracted airway smooth muscle.

力波动引起乙酰胆碱收缩气道平滑肌的重新延长。