MicroRNA 23 Cluster Regulation of Helper T cell Differentiation and Function

MicroRNA 23 簇对辅助 T 细胞分化和功能的调节

• 批准号: 9207095
• 负责人: Heather H Pua
• 金额: $ 5.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207095
• 关键词: Affect; Allergic; Allergic Disease; Alpha Cell; Asthma; Binding; Biological Assay; Biology; CD4 Positive T Lymphocytes; California; Cell Culture Techniques; Cell Differentiation process; Cell physiology; Cells; Cessation of life; Chronic; Chronic lung disease; Clinical; Collaborations; Data Analyses; Development; Disease; Doctor of Philosophy; Effector Cell; Elements; Expenditure; Family member; Fostering; Foundations; GATA3 gene; Gene Targeting; Generations; Genes; Goals; Growth; Healthcare; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IL4 gene; Immune; Immune System Diseases; Immune response; Immunity; Immunology; Immunology procedure; Individual; Infection; Inflammatory Response; Interleukin-13; Interleukin-4; Interleukin-5; K-Series Research Career Programs; Knockout Mice; Knowledge; Lung; Lung Inflammation; Mediating; Medical; Mentors; Mentorship; Messenger RNA; MicroRNAs; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Physicians; Population; Production; Quality of life; Recurrence; Regulation; Regulatory Pathway; Research; Role; San Francisco; Scientist; Site; T-Lymphocyte; Testing; Training; Transcript; Transcriptional Regulation; Universities; Visit; Work; airway hyperresponsiveness; asthmatic; base; cell mediated immune response; cytokine; disorder subtype; human disease; immunoregulation; in vivo; inflammatory lung disease; inhibitor/antagonist; interest; meetings; molecular pathology; mouse model; multidisciplinary; novel; novel therapeutics; overexpression; pathogen; prediction algorithm; public health relevance; response; transcription factor; transcriptome sequencing

 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.

 描述（由申请人提供）：哮喘是一种临床异质性慢性气道疾病，影响7%的美国人口，并导致大量发病率和医疗保健支出。哮喘分子特征的进展导致了疾病亚型的鉴定，从而导致新的治疗方法。许多哮喘患者的疾病是由2型辅助性T（Th 2）细胞驱动的，这种免疫细胞对协调肺部炎症反应至关重要。最近，称为microRNA的分子已被确定为T细胞的关键调节因子。普阿博士的长期目标是确定免疫反应中miRNA介导的调控网络，并确定它们对炎症性肺病的影响。该提案的目的是定义一组特定的microRNA（称为miR-23簇）调节2型免疫反应的机制，并利用这些知识更好地了解过敏性肺炎。由于microRNA通过抑制细胞内的靶基因网络发挥作用，普阿博士假设miR-23簇中的单个microRNA共同作用，限制了Th 2细胞的发育和活性，包括那些导致哮喘发病的细胞。普阿博士将用三个具体目标来检验这一假设。在目标1中，普阿博士将确定由miR-23簇调控的靶基因网络，希望能够识别对2型免疫反应重要的新细胞途径。在目标2中，她将探索microRNA与其靶基因的相互作用如何在特异性调节Th 2细胞功能中发挥关键作用。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/过敏性气道超敏反应和感染的免疫反应中的作用。这个项目是相关的 哮喘以及NIAID的使命，因为它探索了一种新的microRNA介导的调节途径在Th 2细胞，并有可能发现新的治疗途径，涉及microRNA及其靶基因。 普阿博士是一个医学博士谁完成了她的研究生工作在免疫学和临床培训的分子病理学。她目前是加州大学旧金山分校弗朗西斯科的病理学研究员，正在申请K 08指导临床科学家研究职业发展奖。她的培训计划的关键要素，这将有助于支持她成为一名学术医生科学家的目标，包括由T细胞microRNA领域的领先专家Mark Ansel博士指导;由多学科委员会指导，其中包括许多医生科学家以及免疫学和microRNA生物学领域的领导者;数据分析课程;出席促进科学发展和合作的会议;以及专业发展活动。这将为她提供必要的基础，联合收割机结合她的兴趣与她不断增长的专业知识，在分子调节免疫反应的探索和实践的病理学。