Principal Investigator: Kathryn J. Moore, PhD
The overall research focus of my laboratory is to understand: (1) the role of the innate immune system in sterile inflammatory conditions and host defense, and (2) the role of microRNAs in regulating lipoprotein metabolism and atherosclerosis. The innate immune system senses the presence of invading microorganisms and modified endogenous ligands by recognizing conserved molecular structures that are normally absent in the healthy host.
Myeloid cells express classes of pattern recognition receptors, such as the scavenger receptors (SRs) and toll-like receptors (TLRs), that bind conserved a non-selfa patterns to mediate this important function. Although often thought of as a broad, primitive defense mechanism, it is becoming increasingly clear that pattern recognition receptors can cooperate to precisely regulate signaling pathways essential for the proper initiation of innate and acquired immunity.
However, the inappropriate activation of these receptors has also been linked to inflammatory syndromes, including atherosclerosis and Alzheimer's disease. MicroRNAs (miRNAs) represent an elegant mechanism of posttranscriptional control of gene expression that serves to fine-tune biological pathways. These tiny noncoding RNAs (20a 22 nucleotide) bind to the 3' untranslated region of mRNAs, thereby repressing gene expression. Recent advances in the understanding of lipid metabolism have revealed that miRNAs, particularly miR-33, play major roles in regulating cholesterol and fatty acid homeostasis.
Work from our group identified miR-33, an intronic miRNA located with the sterol response element-binding protein (SREBP)-2 gene, as an important regulator of cellular cholesterol efflux, fatty acid I oxidation, and high-density lipoprotein metabolism. Using inhibitors of miR-33, we showed in mice and non-human primates that antagonism of this microRNA increases plasma HDL and reduces VLDL triglycerides. These findings have highlighted the important role that miRNAs play in lipoprotein metabolism and opened new avenues for the treatment of dyslipidemias.