Asthma is a chronic respiratory condition characterized by allergic inflammation of the airways. T helper type 2 (Th2) cells coordinate and amplify allergic inflammation through the secretion of cytokines. The proposed studies address the central hypothesis that microRNAs (miRNAs) expressed by helper T cells regulate cellular functions that contribute to asthma pathology. miRNAs are endogenously expressed ~21nt RNAs that regulate gene expression. It is known that T cells that cannot form any mature miRNAs exhibit defects in proliferation, survival, cytokine production, and differentiation into Th1 and Th2 effector subsets. The challenges that remain are to identify the particular miRNAs that regulate each of these processes, to define their relevance to T cell functions in asthma, and to determine the messenger RNA targets through which these miRNAs mediate their effects.
In Specific Aim 1, we will apply recently developed tools for delivering miRNA mimics and inhibitors into primary mouse and human T cells to perform functional screens that will identify miRNAs that regulate helper T cell functions relevant to asthma. The experiments proposed in Aim 2 will utilize a novel approach for miRNA expression profiling in limiting quantities of starting RNA to discover asthma-associated T cell miRNA expression patterns in clinical samples from highly characterized asthma patient subgroups, and to relate those patterns to clinical features and Th2-associated molecular phenotypes of disease.
In Aim 3, we will characterize the mRNA targets and in vivo function of select miRNAs using genomics and detailed molecular analyses as well as mouse models of asthma. These studies will focus first on 3 strong candidate miRNAs identified in preliminary functional screens and expression profiling.

Public Health Relevance

The simplicity of designing molecules that target specific microRNAs, and recent advances in the delivery of RNA-based therapies, particularly to the lung, has propelled optimism that uncovering the functions of miRNAs in health and disease will lead to rapid development of novel therapies. In this proposal, we focus our efforts on understanding the function of miRNAs in the cells that coordinate the inflammation that underlies asthma, a very common disease with tremendous public health consequences.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109102-02
Application #
8309235
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (02))
Program Officer
Noel, Patricia
Project Start
2011-08-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$180,051
Indirect Cost
$60,624
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pua, Heather H; Steiner, David F; Patel, Sana et al. (2016) MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity 44:821-32
Ramstein, Joris; Broos, Caroline E; Simpson, Laura J et al. (2016) IFN-γ-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells. Am J Respir Crit Care Med 193:1281-91
Schaffert, Steven A; Loh, Christina; Wang, Song et al. (2015) mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function. J Immunol 195:1470-9
Pua, Heather H; Ansel, K Mark (2015) MicroRNA regulation of allergic inflammation and asthma. Curr Opin Immunol 36:101-8
Simpson, Laura J; Ansel, K Mark (2015) MicroRNA regulation of lymphocyte tolerance and autoimmunity. J Clin Invest 125:2242-9
Warth, Sebastian C; Hoefig, Kai P; Hiekel, Anian et al. (2015) Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation. EMBO J 34:1195-213
Baumjohann, Dirk; Ansel, K Mark (2015) Tracking early T follicular helper cell differentiation in vivo. Methods Mol Biol 1291:27-38
Simpson, Laura J; Patel, Sana; Bhakta, Nirav R et al. (2014) A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production. Nat Immunol 15:1162-70
Baumjohann, Dirk; Ansel, K Mark (2014) MicroRNA regulation of the germinal center response. Curr Opin Immunol 28:6-11
Thomas, Molly F; L'Etoile, Noelle D; Ansel, K Mark (2014) Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathways. Trends Genet 30:298-307

Showing the most recent 10 out of 19 publications