Post-transcriptional Mechanisms of Glucocorticoid Anti-inflammatory Action

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中的转录后基因调控（PTR）机制和糖皮质激素的作用机制。候选人是一名非常合格的内科科学家，在学术医学和研究方面有着良好的记录。他从事过各种各样的研究项目，从生物化学到免疫学，并表现出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和富有成效的科学家，以创造性和科学严谨的方法调查疾病相关研究。通过综合方法，该项目将在资深和有经验的共同导师的指导下，在一个由各方面专家组成的科学咨询委员会的指导下，促进候选人的科学和职业发展，并提供额外的培训，以开发小鼠模型并获得新的研究专业知识。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来促进候选人的成功，包括财政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，合作和培养环境，以及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还是消退中。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，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的稳定性并促进炎症，而TTP破坏mRNA的稳定性并传递抗炎作用。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，但可能与炎症的发病机制有关，并具有很大的治疗潜力。为了支持这一点，我们已经证明糖皮质激素（GCs）通过诱导TTP和利用PTR途径来实现抗炎作用。我们的假设是：TTP在调节呼吸道上皮炎症介质中起核心抗炎作用；GCs通过改变TTP和HuR的平衡来降低炎症介质mRNA的稳定性；TTP传递GCs的抗炎作用。通过多学科的方法，本提案将通过以下目标来检验这些假设：利用核糖组学方法在全球范围内鉴定受TTP和HuR调控的mrna库以及GCs对这一过程的影响；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；和3。在选择性消融呼吸道上皮TTP的变应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在哮喘性炎症发病机制和gc机制的认识，为发现新的抗炎靶点打开大门。

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.