Post-transcriptional Mechanisms of Glucocorticoid Anti-inflammatory Action

描述(由申请人提供)：这项建议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，并研究转录后基因调控(PTR)在哮喘气道炎症发病机制和糖皮质激素作用机制中的作用机制。候选人是一名合格的内科科学家，在致力于学术医学和研究方面有着良好的记录。他参与了从生物化学到免疫学的各种研究项目，并展示了生产力和独立的潜力。他的长期职业目标是发展成为一名独立而多产的科学家，以创造性和科学严谨的方法调查与疾病相关的研究。通过综合办法，该项目将在资深和经验丰富的共同导师的指导下促进候选人的科学和职业发展，一个由拟议工作各个方面的专家组成的科学咨询委员会，以及开发鼠标模型和获得新的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，包括财政承诺和研究时间的保护，拥有研究领域专业知识的高级教员，协作和培养环境，以及获得完成项目所需的专门设备和设施。转录后基因调控(PTR)已成为炎症反应调控的核心因素，在炎症反应的建立和消退中都是如此。这一过程可能在呼吸道上皮细胞中特别重要，它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的慢性炎症的核心。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的稳定性并促进炎症，而TTP破坏mRNA的稳定并传递抗炎作用。改变这些影响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，我们已经证明了糖皮质激素(GC)通过诱导TTP和利用PTR途径来发挥抗炎作用。我们的假设是：TTP在调节呼吸道上皮炎性介质中起中心抗炎作用；GCs通过改变TTP/HUR的平衡降低炎症介质的mRNA稳定性；TTP传递GCs的抗炎作用。通过多学科的方法，这项提案将通过以下目标来检验这些假说：1.利用核糖体学方法来全局确定TTP和HUR调节的mRNA池以及GCs在这一过程中的作用；2确定GCs对TTP、HUR和mRNA之间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.在选择性去除呼吸道上皮中TTP的过敏性哮喘小鼠模型中表征炎症反应和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：这项研究将探讨哮喘肺部炎症发病机制以及糖皮质激素的作用机制，糖皮质激素是一种有效的抗炎药。这项工作将确定治疗的新靶点，并加强对导致哮喘的分子事件的理解，哮喘是一种高度流行的疾病。

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.