DESCRIPTION (provided by applicant): Asthma is a clinically heterogeneous chronic airway disease which affects 7% of the US population and results in substantial morbidity and healthcare expenditure. Advances in the molecular characterization of asthma have led to the identification of disease subtypes, leading to novel treatment approaches. Many patients with asthma have disease that is driven by type 2 helper T (Th2) cells, immune cells critical for orchestrating inflammatory responses in the lung. Recently, molecules called microRNAs have been identified as critical regulators of T cells. The long-term goal of Dr. Pua is to identify miRNA-mediated regulatory networks in immune responses and to determine their impact on inflammatory lung diseases. The objectives of this proposal are to define the mechanism by which a specific group of microRNAs, called the miR-23 cluster, regulate type 2 immune responses and leverage this knowledge to better understand allergic lung inflammation. Since microRNAs act by inhibiting networks of target genes within a cell, Dr. Pua hypothesizes that individual microRNAs of the miR-23 cluster act together to limit the development and activity of Th2 cells, including those cells which contribute to the pathogenesis of asthma. Dr. Pua will test this hypothesis using three specific aims. In Aim 1, Dr. Pua will determine the network of target genes regulated by the miR-23 cluster, with the hope of identifying novel cellular pathways important for type 2 immune responses. In Aim 2, she will explore how microRNA interactions with their target genes are critical in specifically regulating Th2 cell function. In Aim 3, Dr. Pu will investigate the role of the miR-23 cluster in regulating human T cells as well as immune responses of asthma/allergic airway hypersensitivity as well as infection. This project is relevant to asthma as well as the mission of the NIAID because it explores a novel microRNA-mediated regulatory pathway in Th2 cells and has the potential to uncover new therapeutic avenues involving microRNAs and their target genes. Dr. Pua is an MD PhD who completed her graduate work in immunology and clinical training in molecular pathology. She is currently a pathology fellow at the University of California, San Francisco, and is applying for a K08 Mentored Clinical Scientist Research Career Development Award. The critical elements of her training plan which will help to support her goal of becoming an academic physician scientist include mentorship by Dr. Mark Ansel, a leading expert in the field of microRNAs in T cells; guidance by a multidisciplinary committee which includes numerous physician scientists as well as leaders in the field of immunology and microRNA biology; coursework in data analysis; attendance at meeting to foster scientific growth and collaboration; and professional development activities. This will provide her the essential foundation to combine her interest with her growing expertise in the molecular regulation of immune responses to the exploration and practice of pathology.

PUBLIC HEALTH RELEVANCE: Asthma is a chronic lung disease that affects 7% of the US population and results in reduced quality of life, recurrent medical visits, and even death in severe cases. The proposed research seeks to investigate a novel group of cellular molecules that regulate the activity of T lymphocytes, a class of immune cells that orchestrate lung inflammation. The results of these studies will not only advance our basic understanding of biology but also provide novel therapeutic strategies in treating allergic diseases such as asthma.