MicroRNA 23 Cluster Regulation of Helper T cell Differentiation and Function

 描述(申请人提供)：哮喘是一种临床上不同种类的慢性呼吸道疾病，影响美国7%的人口，并导致相当大的发病率和医疗保健支出。在哮喘的分子表征方面的进展导致了疾病亚型的识别，导致了新的治疗方法。许多哮喘患者的疾病是由2型辅助T细胞(Th2)细胞驱动的，Th2细胞是在肺部协调炎症反应的关键免疫细胞。最近，被称为microRNAs的分子被确定为T细胞的关键调节因子。Pua博士的长期目标是确定miRNA介导的免疫反应调节网络，并确定它们对炎症性肺部疾病的影响。该提案的目标是定义一组特定的microRNAs(称为miR-23簇)调节2型免疫反应的机制，并利用这一知识更好地了解过敏性肺部炎症。由于microRNAs通过抑制细胞内靶基因的网络发挥作用，Pua博士假设miR-23簇的单个microRNAs共同作用，限制Th2细胞的发展和活动，包括那些参与哮喘发病的细胞。Pua博士将使用三个具体目标来验证这一假设。在目标1中，Pua博士将确定受miR-23簇调控的目标基因网络，希望识别对2型免疫反应重要的新细胞通路。在目标2中，她将探索microRNA与其目标基因的相互作用如何在特定调控Th2细胞功能方面起关键作用。在目标3中，Pu博士将研究miR-23簇在调节人类T细胞以及哮喘/过敏性呼吸道超敏反应和感染的免疫反应中的作用。这个项目很重要 NIAID对哮喘以及NIAID的使命具有重要意义，因为它探索了Th2细胞中一种新的microRNA介导的调控途径，并有可能发现涉及microRNA及其靶基因的新的治疗途径。Pua博士是医学博士，完成了免疫学和分子病理学临床培训的研究生工作。她目前是加州大学旧金山分校的病理学研究员，正在申请K08临床科学家指导研究职业发展奖。她的培训计划的关键要素将有助于支持她成为一名学术内科科学家的目标，包括T细胞microRNAs领域的领先专家Mark Ansel博士的指导；一个多学科委员会的指导，该委员会包括许多内科科学家以及免疫学和microRNA生物学领域的领导者；数据分析方面的课程；出席促进科学增长和合作的会议；以及专业发展活动。这将为她提供必要的基础，将她的兴趣与她在免疫反应分子调控方面日益增长的专业知识结合起来，探索和实践病理学。

 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.