Post-transcriptional Mechanisms of Glucocorticoid Anti-inflammatory Action

糖皮质激素抗炎作用的转录后机制

• 批准号: 8278381
• 负责人: Faoud Terrence Ishmael
• 金额: $ 13.38万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278381
• 关键词: 3' Untranslated Regions; Ablation; Advisory Committees; Anti-Inflammatory Agents; Anti-inflammatory; Area; Asthma; Binding; Binding Sites; Biochemistry; Biological Assay; Cells; Chronic; Co-Immunoprecipitations; Complex; Development; Disease; Environment; Epithelial; Equilibrium; Equipment; Event; Extrinsic asthma; Faculty; Gene Chips; Gene Expression Regulation; Genetic Translation; Glucocorticoids; Goals; Human; Immunology; Immunoprecipitation; Indium; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Knock-out; Laboratories; Lead; Location; Lung; Maps; Measures; Mediating; Medicine; Mentors; Messenger RNA; Methodology; Molecular; Mus; Nuclear; Outcome; Pathogenesis; Pathway interactions; Pennsylvania; Physicians; Play; Process; Productivity; Proteins; Qualifying; RNA; RNA-Binding Proteins; Regulation; Research; Research Project Grants; Resolution; Resources; Role; Scientist; Source; Structure of respiratory epithelium; System; TNF gene; Testing; Therapeutic; Time; Training; Transcript; Transfection; Universities; Work; airway inflammation; antigen challenge; asthmatic airway; career; career development; college; crosslink; cytokine; experience; interdisciplinary approach; mRNA Stability; mRNA Transcript Degradation; mouse model; new therapeutic target; novel; prevent; success

DESCRIPTION (provided by applicant): The overall objectives of this proposal are to provide additional training and laboratory expertise to the candidate and to investigate the mechanisms of post-transcriptional gene regulation (PTR) in the pathogenesis of asthmatic airway inflammation and in the mechanism of action of glucocorticoids. The candidate is a well qualified physician-scientist with a strong track record of commitment to academic medicine and research. He has engaged in a wide variety of research projects, ranging from biochemistry to immunology, and has demonstrated productivity and potential for independence. His long term career goal is to develop into an independent and productive scientist who investigates disease-relevant research with a creative and scientifically rigorous methodology. Through an integrated approach, this project will promote the candidate's scientific and career development with guidance from senior and experienced co-mentors, a scientific advisory committee comprised of experts in various aspects of the proposed work, and additional training to develop a mouse model and acquire new research expertise. The Pennsylvania State University College of Medicine offers a unique environment and mix of resources to promote the success of the candidate, including a financial commitment and protection of research time, senior faculty with expertise in the research area, a collaborative and nurturing environment, and access to specialized equipment and facilities necessary to complete the project. Post-transcriptional gene regulation (PTR) has emerged as a central element in regulation of inflammatory responses, both in the establishment and resolution of inflammation. This process may be of particular importance in the respiratory epithelium, which is now recognized as a major source of inflammatory mediators that are central to the chronic inflammation in diseases like asthma. Two RNA binding proteins (RBPs), TTP and HuR appear to play central roles in the inflammatory response: HuR increases mRNA stability and promotes inflammation, while TTP destabilizes mRNA and conveys anti-inflammatory effects. The interplay and conditions that alter the balance of these effects have not been well characterized, but could be involved in the pathogenesis of inflammation and carry great therapeutic potential. Supporting this, we have demonstrated that glucocorticoids (GCs) deliver anti-inflammatory effects by inducing TTP and exploiting the PTR pathway. It is our hypotheses that: TTP plays a central anti-inflammatory role in the regulation of inflammatory mediators in the respiratory epithelium; GCs decrease mRNA stability of inflammatory mediators by altering the balance of TTP and HuR; and TTP conveys anti-inflammatory effects of GCs. Through a multidisciplinary approach, this proposal will test these hypotheses via the following aims: 1. utilize a ribonomic approach to globally identify the pool of mRNAs regulated by TTP and HuR and the effect of GCs on this process; 2 determine the effect of GCs on the interplay and interactions between TTP, HuR, and mRNA as a mechanism of its anti-inflammatory action; and 3. characterize the inflammatory response and GC- effects in a mouse model of allergic asthma with selective ablation of TTP in the respiratory epithelium. This work will promote the scientific development of the candidate and increase the understanding of PTR in the pathogenesis of asthmatic inflammation and GC-mechanisms, opening the door for discovery of new anti- inflammatory targets. PUBLIC HEALTH RELEVANCE: This research will investigate the mechanisms that underlie the pathogenesis of inflammation in the lung in asthma and mechanisms of action of glucocorticoids, potent anti-inflammatory agents. This work will identify new targets for therapeutics and enhance the understanding of molecular events that lead to asthma, a highly prevalent disease.

描述（由申请人提供）：本提案的总体目标是为候选人提供额外的培训和实验室专业知识，并研究哮喘气道炎症发病机制和糖皮质激素作用机制中的转录后基因调控（PTR）机制。候选人是一个合格的医生，科学家与学术医学和研究的承诺强有力的跟踪记录。他参与了从生物化学到免疫学的各种研究项目，并表现出了独立性和潜力。他的长期职业目标是发展成为一名独立和富有成效的科学家，以创造性和科学严谨的方法研究疾病相关的研究。 通过综合方法，该项目将促进候选人的科学和职业发展，由资深和经验丰富的共同导师指导，由拟议工作各方面专家组成的科学咨询委员会，以及开发小鼠模型和获得新研究专门知识的额外培训。宾夕法尼亚州立大学医学院提供了一个独特的环境和资源组合，以促进候选人的成功，包括财务承诺和研究时间的保护，在研究领域具有专业知识的高级教师，协作和培养环境，以及获得完成项目所需的专业设备和设施。 转录后基因调控（PTR）已成为炎症反应调控的核心要素，无论是在炎症的建立和解决。这一过程在呼吸道上皮中可能特别重要，呼吸道上皮现在被认为是炎症介质的主要来源，而炎症介质是哮喘等疾病慢性炎症的核心。两种RNA结合蛋白（RBP），TTP和HuR似乎在炎症反应中发挥核心作用：HuR增加mRNA稳定性并促进炎症，而TTP使mRNA不稳定并传达抗炎作用。改变这些效应平衡的相互作用和条件尚未得到很好的表征，但可能参与炎症的发病机制并具有巨大的治疗潜力。支持这一点，我们已经证明，糖皮质激素（GC）通过诱导TTP和利用PTR途径提供抗炎作用。我们的假设是：TTP在呼吸道上皮炎症介质的调节中起着重要的抗炎作用; GC通过改变TTP和HuR的平衡来降低炎症介质的mRNA稳定性; TTP传递GC的抗炎作用。 通过多学科的方法，本提案将通过以下目标来测试这些假设：1。利用核糖组学方法来全面鉴定由TTP和HuR调节的mRNA库以及GC对该过程的影响; 2确定GC对TTP、HuR和mRNA之间的相互作用和相互作用的影响，作为其抗炎作用的机制;以及3.通过选择性消融呼吸道上皮中的TTP，表征过敏性哮喘小鼠模型中的炎症反应和GC效应。这项工作将促进候选药物的科学发展，增加对PTR在哮喘炎症发病机制和GC机制中的理解，为发现新的抗炎靶点打开大门。 公共卫生相关性：本研究将探讨哮喘肺部炎症的发病机制和糖皮质激素（强效抗炎药）的作用机制。这项工作将确定新的治疗靶点，并加强对导致哮喘这一高度流行疾病的分子事件的理解。