HuR in Allergic Asthma

过敏性哮喘中的 HuR

• 批准号: 8107658
• 负责人: ULUS ATASOY
• 金额: $ 35.63万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107658
• 关键词: 3' Untranslated Regions; Affect; Allergens; Allergic inflammation; Animal Model; Animals; Area; Asthma; Binding; Biological; Biological Assay; CD4 Positive T Lymphocytes; Cell Nucleus; Cloning; Complex; Cytokine Gene; Cytoplasm; Data; Development; Disabled Persons; Disease; ERG gene; Elements; Employee Strikes; Extrinsic asthma; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Goals; Health; Hypersensitivity; Immunoprecipitation; Incidence; Indium; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Interleukin-5; Knock-out; Lead; Lentivirus Vector; Lung; Lymphocyte; Mediating; Messenger RNA; MicroRNAs; Modality; Modeling; Mus; Operon; Outcome; Ovalbumin; Ovum; Pathogenesis; Phenotype; Play; Prevalence; Production; Proteins; Public Health; Publishing; RNA-Binding Proteins; Regulation; Reporting; Research; Research Personnel; Role; Severities; T-Cell Activation; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translations; Up-Regulation; Work; allergic airway inflammation; base; cDNA Arrays; chemokine; cytokine; design; experience; gain of function; handicapping condition; in vivo; innovation; loss of function; novel strategies; response

DESCRIPTION (provided by applicant): Asthma has been increasing in prevalence and severity for unknown reasons. Though our understanding of the pathophysiology remains poor, it is widely accepted that asthma is an inflammatory disease and CD4+ T cells elaborating Th2 cytokines have been identified as major culprits in its development. Many of these genes are posttranscriptionally regulated but their regulation is not well understood. We have developed a new paradigm, the posttranscriptional operon hypothesis, which states that RNA binding proteins are coordinately regulating the expression of biologically related molecules. Our hypothesis is that the RNA binding protein, HuR, is coordinately regulating Th2 polarization and cytokine gene expression in allergic airway inflammation. HuR is a major stabilizer of labile mRNAs containing AU rich instability elements (AREs) in their 3' untranslated regions. All the Th2 cytokines and 90% of cytokines and chemokines have AREs. 1. Determine effects of HuR modulation upon Th2 polarization and cytokine production in lymphocytes. We will employ lentiviral vectors to under-express HuR in CD4+ T cells and assay Th1/Th2 polarization and cytokine gene expression. 2. Determine role of HuR over-expression and under-expression in murine models of allergic airway inflammation. We will test whether altering HuR levels will modify asthma development in animal models of allergic airway inflammation. 3. Does HuR mediated allergic inflammation involves microRNAs? We will isolate and identify microRNAs from lungs of ova sensitized animals using arrays. Our approach will provide a fuller understanding of the identity and regulation of proinflammatory genes involved in asthma. Better understanding of proinflammatory gene regulation at the posttranscriptional level may potentially lead to targeted therapies to treat asthma. PUBLIC HEALTH RELEVANCE: The reasons for the increasing incidence and prevalence of allergies and asthma worldwide are presently unknown. Exciting new discoveries in posttranscriptional gene regulation and microRNAs potentially may have broad impacts on our understanding of allergen driven asthma. The aim of this proposal is to better understand how cytokine genes are regulated at the posttranscriptional level. This would greatly aid in our understanding of disease pathogenesis and treatment and have a direct impact on public health. PHS 398/2590 (Rev. 09/04) Page 15 Continuation Format Page

描述（申请人提供）：由于未知原因，哮喘的患病率和严重程度一直在增加。尽管我们对病理生理学的理解仍然很差，但人们广泛认为哮喘是一种炎症性疾病，而阐述Th2细胞因子的CD4+ T细胞已被确定为其发育中的主要罪魁祸首。这些基因中的许多基因受到转录后的调节，但其调节尚未得到很好的了解。我们已经开发了一种新的范式，即转录后操纵子假设，该假设指出RNA结合蛋白正在协同调节生物学相关分子的表达。我们的假设是RNA结合蛋白HUR正在协同调节过敏性气道炎症中的Th2极化和细胞因子基因表达。 HUR是在其3'未翻译区域中包含AU丰富不稳定性元素（ARES）的不稳定mRNA的主要稳定器。所有Th2细胞因子和90％的细胞因子和趋化因子均具有ARES。 1。确定HUR调节对淋巴细胞中Th2极化和细胞因子产生的影响。我们将使用慢病毒载体在CD4+ T细胞中表达不足的HUR，并测定TH1/TH2极化和细胞因子基因表达。 2。确定HUR过表达和表达不足在过敏性气道炎症模型中的作用。我们将测试改变HUR水平是否会改变过敏性气道炎症的动物模型中的哮喘发育。 3。HUR介导的过敏性炎症是否涉及microRNA？我们将使用阵列从OVA敏化动物的肺中隔离并鉴定MicroRNA。我们的方法将对涉及哮喘的促炎基因的身份和调节提供更深入的了解。在转录后水平上更好地了解促炎基因调节可能会导致靶向疗法治疗哮喘。公共卫生相关性：目前未知的原因和全球过敏症和哮喘患病率日益增加的原因。转录后基因调节和microRNA中令人兴奋的新发现可能会对我们对过敏原驱动哮喘的理解产生广泛的影响。该提案的目的是更好地了解细胞因子基因如何在转录后水平调节。这将极大地帮助我们理解疾病的发病机理和治疗，并直接影响公共卫生。 PHS 398/2590（修订09/04）第15页延续格式页面