Speaker: Carlos Fernández-Hernando, PhD - Associate Professor (Tenure). Vascular Biology & Therapeutics Program (VBT) Departments of Comparative Medicine and Pathology Integrative Cell Signaling & Neurobiology Metabolism Program (ICSNM) Yale University School of Medicine New Haven – USA
Organizers: IRB Barcelona
Date: Wednesday, 30 May, 13:00h
Place: Aula Fèlix Serratosa, Parc Científic de Barcelona
Cellular and plasma cholesterol levels are maintained through tightly controlled mechanisms, which regulate key metabolic genes both at the transcriptional and post-transcriptional level. Alterations in the control of cholesterol homeostasis can lead to pathological processes, including atherosclerosis, the most common cause of mortality in Western societies. To date, most lipid and lipoprotein research has focused on alterations of protein coding genes, whereas the functions of non-coding RNAs remain largely unknown. Our group originally identified miRNA-33, an intronic miRNA encoded within the intronic sequences of SREBP genes, the master transcriptional regulators that control lipid metabolism. In a number of relevant studies, we were able to demonstrate that miRNA-33 provides a critical link between the regulation of cholesterol biosynthesis by SREBP2 and cholesterol efflux pathways mediated by ABCA1, a transporter that controls cellular cholesterol efflux and high-density lipoprotein (HDL) biogenesis. Most importantly, we found that pharmacological inhibition or genetic ablation of miR-33 increases hepatic ABCA1 expression, circulating HDL-C and attenuates the progression of atherosclerosis. These findings have been reproduced by numerous groups and the application of miR-33 inhibitors for reducing heart disease has been widely recognized and is, in fact, being commercially developed by drug companies. Despite this, some of our subsequent findings have raised questions about possible adverse effects of long-term anti-miR-33 therapies. I will be discussing the novel approaches and mouse models that we are using for assessing the specific role of miR-33 in different tissues, identify physiologically relevant miRNA/target interactions under different physiologic conditions, and directly determine the relative importance of specific miRNA target interactions by genetically disrupting miRNA binding sites within individual target genes in vivo using CRISPR- Cas9 genome editing. Furthermore, we will discuss the development of novel therapeutic approaches for targeting of miR-33 in specific tissues including establishing a system to direct anti-miR-33 therapeutics to atherosclerotic plaques and employing techniques for disrupting specific miRNA/target interactions in vivo.
Molecular Medicine Programme Seminar