Where RNA biology meets human disease
The McManus lab studies basic biological processes relating to an important cellular pathway called RNA interference (RNAi), using cultured cells and the mouse as a model. This includes the study of small (18-26 nucleotide) regulatory RNAs of biological significance, such as microRNAs, and the factors involved in small RNA production and activity. In the past few years many groups have published the sequences thousands of microRNAs from plants to humans and this number is growing. In fact, approximately 5% of all known human genes encode microRNAs, yet we know very little about their function. Our lab is interested in understanding how microRNAs contribute to the specification of cell fate and function, and how deregulation of microRNAs may contribute to human disease.
Models for studying noncoding RNAs. We have generated a mouse knockout for the gene called Dicer, which is the catalytic engine of small RNA production in cells. We have used this mouse to explore the role of small RNAs in many tissues and it is clear that they are key for normal cellular function. However this is a low-resolution model, since all microRNAs are simultaneously depleted. For this reason, hundreds of conditional mouse small RNA knockout models are individually being made and studied in collaboration with others at UCSF. These studies will illuminate the role of small RNAs in basic biology and human disease.
Dissecting genetic pathways for RNA biology. We are working hard to translate our basic research findings to our clinical and disease-centric colleagues at UCSF. We believe that the small regulatory RNAs that have been discovered are just the 'tip of the iceberg' in a set of important biology that we are far from understanding. Based on our studies of this biology, we have developed cutting-edge research tools and agents that usurp this pathway for the interrogation of gene function and the potential use in the intervention of human disease. RNAi is significantly impacting the speed at which we can validate and deliver drugs to the clinic, and it very likely constitutes the next frontier in human therapeutics.