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 37 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; an NIH MERIT Award, 1997-2005; 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 inflammatory and metabolic diseases

Many major human diseases such as diabetes, atherosclerosis and rheumatoid arthritis are promoted by dysfunctions in inflammatory pathways. Macrophages 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. Experiments in our laboratory are currently devoted to 1.) applying RNAi-based approaches to identify target genes in macrophages, adipocytes and other cells that promote these diseases, and 2.) developing strategies for therapeutic application of RNAi against these targets.

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 is one over-riding roadblock to the general use of siRNA as a medicine for human disease: safe, effective delivery to specific target tissues or cell types in vivo.  Achieving the goal of an oral delivery system for synthetic siRNA, in particular, could potentially transform the practice of medicine.

Our laboratory is engaged in collaborative experiments with Dr. Gary Ostroff’s group to achieve orally delivered siRNA as an effective therapeutic strategy for inflammatory pathways. We are employing unique encapsulation technology that both protects siRNA through the digestive tract and directs its uptake by macrophages and dendritic cells where it silences genes involved in pathogenic inflammation.

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. Finally, we are using high resolution ultrafast TIRF microscopy to study the cellular trafficking pathways whereby insulin controls the glucose transporter protein (GLUT4) that mediates glucose disposal in skeletal muscle and adipose tissue.

Figure Legend

Hypothesis: The protein kinase Map4k4 promotes insulin resistance by mediating cytokine production in macrophages and insulin resistance in adipocytes and skeletal muscle. 

We discovered the protein kinase Map4k4/NIK as a negative regulator of insulin signaling and adipogenesis by employing an RNAi screen in mouse adipocytes (PNAS  103; 2087-2092, 2006). Map4k4 appears to be a mediator of some effects of the TNF-a signaling pathway, and is a negative regulator of PPARg expression in adipocytes. Subsequently, a paper appeared indicating the Map4k4 is also a negative regulator of insulin signaling in skeletal muscle of type 2 diabetics (J. Biol. Chem. 282; 7783-7789, 2007). We have more recently discovered that Map4k4 mediates cytokine expression and secretion in macrophages. Thus this protein kinase represents an exciting potential therapeutic target for inflammatory diseases and diseases where macrophages play a pathogenic role, e.g., diabetes, atherosclerosis, rheumatoid arthritis and inflammatory bowel diseases.