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.
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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