Michael P. Czech, PhD

Michael P. Czech is The Isadore and Fannie Foxman Chair of Medical Research in the Program in Molecular Medicine at UMass Chan Medical School. He earned his PhD degree in biochemistry in 1972 at Brown University under the mentorship of Professor John Fain, and completed postdoctoral study in the Biochemistry Department at Duke University Medical Center. Dr. Czech moved to UMass Chan as Professor and Chair of the Department of Biochemistry in 1981 and served as the founding Chair of the Program in Molecular Medicine from 1989-2018. His research addresses mechanisms of signal transduction, metabolism and insulin resistance in type 2 diabetes and obesity. The Czech lab has applied RNAi and CRISPR techniques to discover novel drug targets and to develop therapeutic strategies for alleviating these metabolic diseases and nonalcoholic steatohepatitis.

Dr. Czech has served on several editorial boards and NIH Study Sections and is a member of the Scientific Review Board of the Howard Hughes Medical Institute. He has received the Scientific Achievement Award (1982), the Banting Medal (2000) and the Albert Renold Award for mentorship (2004) from the American Diabetes Association, the David Rumbough Scientific Award from JDRF (1985), NIH MERIT Awards (1997-2005 and 2012-2022) and the Elliot P. Joslin Medal (1998). 

Major Area of Investigation

Gene editing & deletion to enhance insulin signaling and energy expenditure in type 2 diabetes and obesity
 

Central Questions for the Czech Lab

• Can we identify molecular mechanisms that disrupt insulin signaling in obesity and type 2 diabetes to develop therapeutic strategies for these diseases?
• Can we identify and modulate molecular mechanisms that switch adipocytes from storing triglyceride to cells that oxidize fat, expend energy and secrete beneficial factors?
• Can we target genes that promote fatty liver and inflammation in obesity and diabetes with therapeutic siRNA to alleviate nonalcoholic steatohepatitis (NASH)?

A complete list of Dr. Czech's published work can be found in My Bibliography

Current Research 

Many of our projects utilize CRISPR and RNA interference (RNAi) to selectively silence normal or disease genes in vivo, providing powerful research tools & potential therapeutic approaches. Experiments in our lab are devoted to developing CRISPR- and siRNA-based delivery particles that can beneficially alter gene expression in adipocytes, hepatocytes and other cell types. Using these techniques, we have recently shown that gene editing of adipocytes by CRISPR can enhance their energy expenditure and fat oxidation. These efforts are advancing toward therapeutic applications. 

Another approach we have developed in collaboration with the Gary Ostroff laboratory is a method to deliver siRNA in vivo using glucan encapsulation vehicles (GeRPs) that can target macrophages in adipose tissue and liver to silence genes and attenuate tissue inflammation and insulin resistance (see Figure below and some of our recent publications with this technology).

(Figure) Color coded scanning electron microscope image of siRNA-containing GeRPs (green) being bound to macrophages (maroon) prior to being engulfed by the cells and mediating gene silencing in vitro. Current experiments are designed to incorporate CRISPR technology into this strategy. Listed are recent publications from our laboratory using this technology to silence genes in vivo. See our data in BioRxiv.

Contributions to Science

Identification of subunit  configurations of the receptors for insulin and the insulin-like growth factors

Prior to the 1980s there was an appreciation that receptor proteins for these peptides were present on cell surface membranes, but there was no biochemical information on these receptors. To approach this problem, Paul Pilch, then a postdoc in our lab, synthesized disuccinimidyl suberate as an affinity-labeling reagent for peptide hormone receptors and identified the two insulin receptor subunits, denoting these as alpha and beta in several publications. This approach was then used to deduce the disulfide-linked subunit configurations of the receptors for insulin and the insulin-like growth factors (IGF). This work clarified the overlapping binding affinities of insulin and the IGF ligands for these receptors and revealed that the IGF-2 receptor does not mediate the major bio-effects of these peptides.  We showed the IGF-2 receptor is instead a target of insulin signaling, cloned the IGF-2 receptor in collaboration with Axel Ullrich and reported in Science it is identical to the mannose-6-phosphate receptor, i.e., it is a bi-functional receptor. This affinity crosslinking technology was then successfully extended to other systems, most notably to the transforming growth factor receptors by one of my former fellows, Dr. Joan Massague.

2. Puri, V., Ranjit, S., Konda, S. Nicoloro, S.M., Straubhaar J, Chawla, A., Chouinard, M., Lin, C., Burkart A, Corvera, S., Perugini, R.A., Czech, M.P.(2008) Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc. Nat. Acad. Sci. USA 105(22): 7833-7838. PMC2409392.

3. Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, Vigouroux C, Magré J, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O'Rahilly S,Savage DB; LD Screening Consortium.(2009) Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med. 1(5) 280-7. PMC2891108.

4. DiStefano MT, Danai LV, Roth Flach RJ, Chawla A, Pedersen DJ, Guilherme A, Czech MP. (2015) The lipid droplet protein Hypoxia-inducible gene 2 promotes hepatic triglyceride deposition by inhibiting lipolysis. J Biol Chem., 290 (24) 15175-84. PMID: 25922078.

Development of siRNA delivery technology for research and therapeutic strategies

A major area of our research addresses the cellular and molecular mechanisms of inflammation and metabolic disease, especially obesity and diabetes. Recognizing the power and potential of RNAi as a therapeutic tool, we developed siRNA screens and identified Map4k4 and RIP140 as metabolic regulators. Our group then collaborated with Gary Ostroff to develop a novel siRNA delivery system (GeRPs) based on yeast cell wall glucan shells to encapsulate siRNA cargo. This system delivers siRNA specifically to phagocytic cells in vivo, and we have demonstrated silencing of inflammatory genes in mouse macrophages following administration in vivo. We have now published extensively on the effectiveness of siRNA silencing in vivo using GeRPs, in papers by our laboratory and in collaboration with other research groups. Thus this technology can now be transferred successfully to other laboratories, which have independently reproduced our gene silencing results. We are particularly excited about our recent work showing gene silencing in selective subpopulations of macrophages in visceral adipose tissue and in Kupffer cells in the liver. These data show that tissue- localized macrophages and macrophage-like Kupffer cells do indeed release deleterious cytokines and factors that cause insulin resistance, but also play beneficial roles in cell physiology. This work has been extended to the use of “self delivery” sdRNA and development of vehicles for delivery of CRISPR-based gene editing.

1. Powelka AM, Seth, A, Virbasius, JV, Kiskinis, E, Nicoloro, SM, Tang, X, Straubhaar, J, Cherniack, AD, Parker, MG, Czech, MP. (2006) Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. Journal of Clinical Investigation. 116(1):125-136. PMID 16374519.

2. Roth Flach RJ, Skoura A, Matevossian A, Danai LV, Zheng W, Cortes C, Bhattacharya SK, Aouadi M, Hagan N, Yawe JC, Vangala P, Menendez LG, Cooper MP, Fitzgibbons TP, Buckbinder L, Czech MP. (2015) Endothelial protein kinase Map4k4 promotes vascular inflammation and atherosclerosis.  Nature Communications. 6:8995. PMID 26688060.

 3. Aouadi M, Tencerova M, Vangala P, Yawe JC, Nicoloro SM, Amano SU, Cohen JL, Czech MP. (2013) Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci U S A. 110(20): 8278-8283. PMC3657808.

4. Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, Tam J, Han T, Mukhopadhyay B, Skarulis MC, Ju C, Aouadi M, Czech MP, Kunos G. (2013) Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nature Medicine. 19(9):1132-1140. PMC4050982.

Graduate Student Rotation & Thesis Research Projects

Developing CRISPR technology for gene editing in adipocytes

Adipocytes function as master regulators of whole body metabolism and deletions of specific genes in knockout mice promote dramatic improvements in glucose tolerance and insulin sensitivity in diabetic models. Thus the ability to direct gene editing in adipocytes in vivo has great potential in developing therapeutic strategies for obesity, type 2 diabetes and cardiovascular complications. Alternatively, an ex vivo approach is also feasible since adipose cells can be genetically altered in vitro prior to implantation into mice with beneficial effects. Such projects are designed to be performed in collaboration with other Czech lab members with the goal of specifically deleting or editing genes in adipose depots that drive increases in fatty acid oxidation, energy expenditure and systemic metabolic activity. Exciting preliminary data at the “proof of principle” stage has been achieved and this project is designed to focus on specific genes of high interest for therapeutics.

Mentoring

The Czech lab actively mentors graduate students and postdoctoral fellows. Many former students and postdoc trainees from our lab are now internationally recognized professors at major universities and medical schools. They include:

Paul Pilch, Professor of Biochemistry, Boston University School of Medicine

Jeffrey Pessin, Professor and Director of the Diabetes Center, Einstein College of Medicine

Joan Massague, Director, Sloan Kettering Institute

Roger Davis, HHMI investigator and Professor of Molecular Medicine, UMass Chan Medical School

Silvia Corvera, Professor of Molecular Medicine, UMass Chan Medical School

Carla Greenbaum, Vice Chair and Director of Clinical Research, Benaroya Research Institute

Jes Klarlund, Professor of Ophthalmology, University of Pittsburgh Medical Center

Rob Lewis, Professor of Biochemistry and Molecular Biology, Eppley Cancer Institute, University of Nebraska Medical Center

Richard MacDonald, Professor of Biochemistry and Molecular Biology, Eppley Cancer Institute, University of Nebraska Medical Center

Assia Shisheva, Professor of Physiology, Wayne State School of Medicine.

Mark Sleeman, Professor of Physiology, Monash University, Australia

John Harris, Associate Professor of Medicine, UMass Chan Medical School

Zhen Jiang, Associate Professor of Pharmacology and Medicine, Boston University

Vishu Puri, Professor of Biomedical Sciences, Ohio University

Olga Gupta, Assistant Professor of Pediatrics and Medicine, University of Texas Southwestern Medical Center

Tim Fitzgibbons, Assistant Professor of Medicine, UMass Chan Medical School

Myriam Aouadi, Assistant Professor, Integrated Cardio Metabolic Centre, Karolinska Institute

Adilson Guilherme, Associate Professor of Molecular Medicine, UMass Chan Medical School