Academic Background

Michael P. Czech is Professor and founding Chair of the Program in Molecular Medicine, University of Massachusetts Medical School. Molecular Medicine currently includes 43 faculty research laboratories, several Howard Hughes Investigators and over 400 scientists and staff. His research addresses mechanisms of signal transduction and insulin resistance in type 2 diabetes and obesity. His laboratory has recently applied RNAi to discover novel drug targets and to develop therapeutic strategies for alleviating inflammatory and metabolic diseases.

Dr. Czech earned the PhD degree in biochemistry in 1972 at Brown University, and completed postdoctoral study at Duke University Medical Center. He became Assistant Professor at Brown in 1974, rising to the rank of Professor in 1980. In 1981 Dr. Czech moved to the University of Massachusetts Medical School as Professor and Chair of the Department of Biochemistry and Molecular Pharmacology, which he led until his appointment as Director of Molecular Medicine in 1989.

Dr. Czech has authored approximately 275 publications, serves on several editorial boards, and has served on several NIH Study Sections and Review Panels of the Howard Hughes Medical Institute. He has received the Outstanding Scientific Achievement Award of the American Diabetes Association, 1982; the David Rumbough Scientific Award of the Juvenile Diabetes Foundation in 1985; NIH MERIT Awards, 1997-2005 and 2012-2018; the Elliot P. Joslin Medal in 1998, the 2000 CIIT Founder’s Award, the 2000 Banting Medal and the 2004 Albert Renold Award of the American Diabetes Association.

RNAi-based therapeutic strategies for diseases of inflammation and metabolism

Many major human diseases such as diabetes, atherosclerosis and rheumatoid arthritis are promoted by excessive or dysfunctional inflammation within specific tissues. Macrophages and dendritic cells are central players in such diseases based on their ability to express antigenic peptides on their cell surfaces and secrete cytokines that attract and activate immune cells. The ability of double stranded RNA to act through RNA interference (RNAi) pathways to selectively silence normal or disease genes in vivo provides both a powerful research tool and potential approach to therapies. Experiments in our laboratory are currently devoted to 1.) applying RNAi-based screens and other methods to identify target genes in macrophages, endothelial cells and adipocytes that promote inflammation and metabolic disease, and 2.) developing strategies for therapeutic application of RNAi against these targets in such diseases.

Unlike small molecule drugs, RNAi can target human genes without regard to the nature of the protein structure of the gene product. As a consequence, all genes become potential targets for RNAi-based therapies. However, there are over-riding roadblocks to the general use of short interfering RNA molecules (siRNA) as medicines for human disease. These include effective delivery to specific target cell types in vivo and toxicities of chemically modified siRNA species or their delivery vehicles. Developing delivery systems for siRNA that target specific tissues for gene silencing in a safe way could bring exciting new therapies to the clinic. Achieving the goal of a safe oral delivery system for therapeutic siRNA, in particular, could potentially transform the practice of medicine.

Our laboratory is engaged in experiments designed to lead to the successful development of siRNA-based therapeutics. We employ encapsulation technology to imbed siRNA into non-toxic glucan particles that both protect the siRNA during administration in vivo as well as direct its uptake specifically into macrophages and dendritic cells. We have demonstrated that this method can be effective in mice to silence genes that promote inflammation. We are continuing to improve the delivery system by reducing the number of components and improving release of the siRNA, and we are testing its efficacy in several disease models including diabetic mice.

Other projects in our laboratory address the underlying mechanisms whereby inflammation and other processes impair insulin signaling in obesity and type 2 diabetes. We are investigating the roles of lipid droplet proteins in regulating adipocyte metabolism and whole body glucose tolerance using mouse knockout models and adipose samples from human subjects. Our studies are also directed towards understanding the signaling pathways whereby the protein kinase Map4k4 acts to cause insulin resistance. We have discovered roles of Map4k4 in suppressing lipogenesis in adipocytes while promoting cytokine and adhesion molecule expression by macrophages and endothelial cells, respectively. Our data suggest that Map4k4 could be a potential drug target for metabolic disease and atherosclerosis.

Encapsulation of siRNA and amphipathic peptide endoporter in micron sized glucan shells prepared from yeast by solvent and acid/base extractions. See cited reference in the Figure for details of preparation and use of this siRNA delivery system for gene silencing in vivo.