Validating CCL28 as a Target for Novel Asthma Therapies using NMR Spectroscopy

Medical College Of Wisconsin, Milwaukee WI

Investigators

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Abstract

PROJECT SUMMARY Asthma is one of the most common chronic diseases worldwide. It is characterized by episodic airflow obstruction and debilitating clinical symptoms including wheezing, coughing, and shortness of breath. Asthma commonly begins in childhood, causing excessive lung inflammation early in life that leads to poor lung development and chronically reduced lung function. While most asthmatic individuals have mild disease that is symptomatically controlled with bronchodilators and anti-inflammatory drugs, a significant number have severe disease that is refractory to all available therapies. Though the pathogenesis of asthma remains unclear, an emerging paradigm supports the notion that an immune cascade stimulated by a respiratory viral infection early in life may play a critical role. Further, there is evidence to suggest that this ?viral-induced asthma? pathway is critically dependent on the human chemokine CCL28. CCL28 thus represents an exciting and novel target for the development of alternative asthma therapeutics. I hypothesize that a thorough structural and mechanistic understanding of CCL28 and CCL28-receptor interactions will guide the development of future, potentially curative asthma therapeutics. The goals of this fellowship are to characterize the structural and molecular mechanisms by which CCL28 can drive asthma pathology and to validate CCL28 as a target for future asthma therapeutics. The fellowship research will be divided into two specific aims: 1) Test the hypothesis that CCL28 drives asthma phenotypes via a common binding interaction with its two receptors; 2) Test the hypothesis that CCL28?s asthma-inducing activity can be inhibited by small molecule ligands that disrupt CCL28-receptor interactions. Completion of this fellowship proposal will yield important structural and mechanistic information that will further our understanding of asthma. In addition, targetable sites on CCL28 will be identified and small molecule ligands of CCL28 will be discovered with the potential to one day be translated into clinically useful asthma therapeutics.