Analysis of novel molecular networks underlying mast cell development, function and disease: specific roles of CD25, NF-kB p50 and microRNAs

Mast cells are cells of the immune system that have important regulatory functions, and contribute to the elimination of parasites, bacteria and the detoxification of venoms. They are key effector cells in allergic and asthmatic diseases, and when dysregulated, they can also give rise to mastocytosis, a tumor characterized by the abnormal proliferation and accumulation of aberrant mast cells in various tissues. When mastocytosis develops into aggressive forms, its clinical course can be very rapid and often fatal, hence the importance of uncovering new molecular mechanisms at the base of the development of this disease, as well as of identifying new molecular markers for diagnosis and prognosis. MicroRNAs (miRNAs) are small molecules that recently emerged as major players in the regulation of gene expression in the immune system. While the importance of miRNAs in various systems and diseases is by now well established, very little is known about the role of miRNAs in normal mast cell development and function or in mast cell-related diseases. Our laboratory identified a class of miRNAs (miR-221/-222) that are important regulators of multiple processes in mast cells. Most importantly, the cell surface receptor CD25 is regulated by miR-221/-222. CD25 is one of the most reliable diagnostic markers for systemic mastocytosis, but its role in mast cell biology and disease is unknown. With this project we therefore want to analyze the role of CD25, miR-221/-222 and other miRNAs in mast cell development and function as well as in mastocytosis. We also found that another miRNA, miR-146a, modulates mast cell survival and death in a molecular circuitry that also involves the transcription factor NF-kB p50. Our second aim is to continue investigating the molecular network involving NF-kB p50 and miR-146a in regulating normal and pathologic mast cell functions. Overall, our studies will provide insights on the role of miRNAs in mast cells, and lay the groundwork for understanding some of the mechanisms underlying pathologic conditions caused by mast cells, such as allergy and mastocytosis.