Post-transcriptional Mechanisms of Glucocorticoid Anti-inflammatory Action

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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.