Project 2: Role of miRNAs in Th2-Driven inflammation in Asthma Summan/ 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 -21 nt 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 Thi 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 will utilize a novel approach for mIRNA expression profiling In limiting quantities of starting RNA tp discover asthma-associated T cell mlRNA expresssion 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. The experiments proposed In Aim 2 will apply recently developed tools for delivering miRNA mimics and inhibitors into primary mouse and human T cells to perform functional screens that will Identifv mIRNAs that requlate helper T cell functions relevant to asthma.
In Aim 3, we will Identifv bona fide functionally relevant mRNA targets of miR- 29 using bioinformatic, genomic, and biochemical analyses to Inform limited sIRNA screens. In addition, we will assess the In vivo function on mlR-29 In a house dust mite extractinduced mouse model of asthma.

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 Program Projects (P01)
Project #
5P01HL107202-02
Application #
8526523
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$333,887
Indirect Cost
$121,220
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Mohapatra, A; Van Dyken, S J; Schneider, C et al. (2016) Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol 9:275-86
Gordon, Erin D; Locksley, Richard M; Fahy, John V (2016) Cross-Talk between Epithelial Cells and Type 2 Immune Signaling. The Role of IL-25. Am J Respir Crit Care Med 193:935-6
von Moltke, Jakob; Ji, Ming; Liang, Hong-Erh et al. (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529:221-5
Fahy, John V (2016) Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress. Ann Am Thorac Soc 13 Suppl 1:S78-82
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
Wesolowska-Andersen, Agata; Seibold, Max A (2016) Is the Road to Precision Medicine in Chronic Lung Disease Paved with Degraded Chitin? Am J Respir Crit Care Med 193:107-8
Gordon, Erin D; Simpson, Laura J; Rios, Cydney L et al. (2016) Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci U S A 113:8765-70
Gordon, Erin D; Palandra, Joe; Wesolowska-Andersen, Agata et al. (2016) IL1RL1 asthma risk variants regulate airway type 2 inflammation. JCI Insight 1:e87871
Reber, Laurent L; Fahy, John V (2016) Mast cells in asthma: biomarker and therapeutic target. Eur Respir J 47:1040-2
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

Showing the most recent 10 out of 61 publications