University of North Carolina At Chapel Hill
Grant: $500,000 - Department of Health and Human Services - Sep. 18, 2009
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Award Description: Micro RNA Regulation of Human Airway Epithelial Phenotype – ARRA Greater than (<) 22 million people in the USA currently have asthma and <15 million people have chronic obstructive pulmonary disease. Along with less common obstructive lung diseases such as cystic fibrosis, non-CF bronchiectasis and primary ciliary dyskinesia, these conditions place massive burdens on health care resources and human spirit. These diseases are focused on the lung airways, which become inflamed, remodeled, and obstructed, decreasing lung function. The protective airway epithelium is strategically located at the lung-environment interface where it initiates, integrates and orchestrates host immune responses and airway remodeling. Phenotypic changes in the airway such as enhanced epithelial shedding and turnover, deficient repair, mucous secretory (goblet) cell hyperplasia and squamous metaplasia are variably present and are integral to the progression of inflammatory, obstructive airway diseases. Despite recent advances, many basic mechanisms regulating altered structure and function of human bronchial epithelial (hBE) cells remain poorly understood, and there are no specific therapies directed at preventing or reversing disease-related phenotypic changes in the airway epithelium. Micro RNA’s (miRNAs) play a vital regulatory role in many cell processes- their expression is highly cell type and differentiation stage-specific. Although hBE cells are central participants in the pathogenesis of several extremely important lung diseases there is minimal miRNA data in this key cell type. In vitro model systems recapitulating in vivo structure and function are critical milestone tests for therapeutic development and translation. Our group is uniquely poised to provide a comprehensive picture of the miRNA repertoire in hBE cells and their expression pattern and cell localization during normal differentiation and in a series of highly relevant disease models. Accordingly, Aim 1 is to 'Develop a comprehensive portrait of miRNA expression in hBE cells during normal differentiation and in a spectrum of relevant injury/repair conditions . We will also perform mRNA arrays from the identical cell cultures in order to elucidate miRNA:gene expression networks. Novel miRNA discovery by sequencing, high throughput screening of miRNA arrays, qRT-pCR and robust northern blots in Aim 1 will allow for rigorous identification and quantitation of hBE cell miRNAs, but they must be complemented by over-expression and inhibition studies in order to determine functional effects. These studies are challenging in hBE cells, but are key for establishing whether modulating miRNAs can change phenotype for potentially beneficial therapeutic purposes. The goal of Specific Aim 2 is to 'Determine functional consequences of manipulating expression of candidate miRNAs in hBE cells . In summary, we will comprehensively determine the miRNA repertoire of a key lung cell type, hBE cells, and will test the function of novel and/or highly regulated miRNAs to change hBE cell structure and function. We will create a valuable database and a platform for critical milestone testing of improved treatments for lung diseases that afflict greater than 30 million Americans.
Project Description: October 5, 2009 progress report for Micro RNA Regulation of Human Airway Epithelial Phenotype– ARRA. We note the September 18, 2009 e-mail Notice of Award indicating a September 24, 2009 start date. In this short time, we had a strategic meeting of the Principal Investigators (Drs. Hammond, Hayes and Randell), and have scheduled regular ongoing meetings of the entire research group, which will occur every other Thursday beginning October 8, 2009 in the UNC Cystic Fibrosis Center Conference Room. The initial technical topic of discussion included the decision to replicate the cultures, RNA harvest and characterization (histology including mitotic index) of the time course and response to bacterial product studies in Aim 1A, parts 1 and 2. Furthermore, we have decided to use existing time course miRNA expression data to begin the mimic and inhibitor and in situ hybridization expression studies. We have have identified critical staffing needs and will at least employ two existing staff members part time (Mr. Clapp and Dr. Wilkinson) until such time as full time replacements can be recruited. Accordingly, we are organizing a search for two technicians and a post-doctoral fellow and have interviewed one post-doctoral fellow candidate. We have contacted subcontractors and suppliers about optimal strategies and costs for mRNA and miRNA profiling and for miRNA in situ hybridization. Experimentally we have conducted harvest of large quantities of mRNA from early and late time-course hBE cultures and have performed our first deep-sequencing runs, the results of which are the subject of our first group lab meeting. We have identified the hBE cell stocks from which to begin the imminent culture work. These activities indicate a good initial start towards accomplishing the project goals.
Jobs Summary: Since this project has just started on very short notice at the very tail of the quarter, we have not yet created new hires nor have we expended funds to retain existing staff during this quarter. However, we are retaining current staff part time on the project and these will be billed to this project as applicable. Furthermore, we are actively searching for technicians and a post-doctoral fellow and anticipate that at least 3 FTE's will be supported by the project on an ongoing basis beginning next quarter. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
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