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.
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.
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