Role of microRNAs in the development and function of cells of the immune system
MicroRNAs (miRNAs) are a growing class of endogenous small non-coding RNAs that regulate gene expression by binding through partial base-pairing to target messenger RNAs and inducing translational repression, cleavage or destabilization of the target mRNA. Because each miRNA potentially can regulate expression of a distinct set of genes, it is conceivable that the differential expression of different miRNAs might profoundly influence the repertoire of genes that are expressed during development, differentiation or disease. Altered levels of miRNAs have been described in several human malignancies, including leukemias and lymphomas, but our knowledge of the regulation and biology of miRNAs is far from being comprehensive. Furthermore, their mechanism of action and the genes that they target are still not completely known or understood. We have performed a high-throughput analysis of miRNA expression in diverse murine hematopoietic cell types (Monticelli, S. et al., MicroRNA profiling of the murine hematopoietic system. Genome Biol., 2005). Following up on those studies, we identified a family of miRNAs (miR-221-222) with a potential role in mast cells development and functions. In particular, our preliminary data show that miR-221-222 affect cell proliferation; it is also known that these miRNAs regulate c-KIT expression, a surface receptor required for erythropoiesis, mast cells and melanocytes development. To further investigate the role of these miRNAs in the proliferation and development of mast cells, as well as to identify new regulatory miRNAs in other cells of the immune system, I propose: Aim 1. To investigate the role of miR-221-222 in mast cell biology and mastocytosis; Aim 2. To continue expanding my previous miRNA expression analysis to other cell types in the immune system, in particular T lymphocytes. Besides being of fundamental relevance to our understanding of cell differentiation and gene regulation, elucidation of the molecular mechanisms that control mast cells and T helper cell differentiation and activation have substantial potential for clinical application in the treatment of asthma, allergy, autoimmunity, chronic inflammation and malignancies.