Michael P. Czech, PhD

Professor, Program in Molecular Medicine
Isadore and Fannie Foxman Chair of Medical Research

Michael CzechDr. Czech was Chair of the Department of Biochemistry from 1981 to 1989, and was the founding Chair of the Program in Molecular Medicine (1989-2018).  He earned the PhD degree in biochemistry in 1972 at Brown University under the mentorship of Professor John Fain, 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. His research addresses mechanisms of signal transduction, metabolism and insulin resistance in type 2 diabetes and obesity. Czech’s laboratory has recently applied RNAi and CRISPR techniques to discover novel drug targets and to develop therapeutic strategies for alleviating inflammatory and metabolic diseases.

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 of the Juvenile Diabetes Foundation (1985); NIH MERIT Awards (1997-2005 and 2012-2022); the Elliot P. Joslin Medal (1998), and the Jacobaeus Prize awarded in Umea, Sweden in 2009.

Major Area of Investigation

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

Central Questions for 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)?

Publications

A complete list of my published work can be found in My Bibliography 

Current Research 

Many of our projects take advantage of CRISPR and RNA interference (RNAi) to selectively silence normal or disease genes in vivo, providing both powerful research tools and potential approaches to therapies. Experiments in our laboratory are currently 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 that we have developed in collaboration with the Gary Ostroff laboratory is a method to deliver siRNA in vivo using glucan encapsulation vehicles (GeRPs).  GeRPs 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.

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.

1. Pilch, P.F. and Czech, M.P. (1979). Interaction of Cross-Linking Agents with the Insulin Effector System of Isolated Fat Cells.  Covalent Linkage of 125I-Insulin to a Plasma Membrane Receptor Protein of 140,000 Daltons. J. Biol. Chem., 254: 3375-3381. PMID: 429356.

2. Massague, J and Czech, M.P. (1982). The Subunit Structures of Two Distinct Receptors for Insulin-Like Growth Factors I and II and Their Relationship to the Insulin Receptor.  J. Biol. Chem., 257: 5038-5045. PMID: 6279656.

3. MacDonald. R.G., Pfeffer, S.R., Coussens, L., Tepper, M.A., Brocklebank, C.M., Mole, J.E., Anderson, J.K., Chen, E., Czech, M.P. and Ullrich, A. (1988) A Single Receptor Binds both Insulin-like Growth Factor II and Mannose-6-Phosphate.  Science, 239: 1134-1137. PMID: 2964083.

Identification of a key downstream target of insulin-stimulated PIP3 generation. As several groups identified PI 3-kinase as a component in insulin signaling, it became important to identify downstream signaling elements. Our group established an expression cloning screen for identifying targets of the PI 3-kinase pathway in insulin and IGF-1 receptor signaling, and discovered Grp1, a novel downstream effector of the signaling lipid PtdIns(3,4,5)P3 (PIP3). We reported in Science the identification of Grp1, showing that it defines a novel PI 3-kinase-mediated signaling pathway distinct from Akt, linking PIP3 to the activation of ArfGTPases. Jes Klarlund in our lab showed the Grp1 PH domain has the highest specificity for PIP3 of all the PH domains studied.  The structural basis of selective PIP3 binding to the crystallized PH domain of Grp1 was solved in collaboration with David Lambright, published in Molecular Cell.  The Grp1 PH domain fused to GFP is also now  widely  used by  researchers  as  a  unique  reagent  to  define  the  generation  of  PIP3  at  the  plasma membrane.

1. Klarlund, J., Guilherme, A., Holik, J.J., Virbasius, J.V., Chawla, A., Czech, M.P. (1997). Signaling by 3,4,5-Phosphoinositide   through   Proteins   Containing   Pleckstrin   and   Sec7   Homology   Domains. Science, 275, 1927-1933. PMID: 9072969.

2. Lietzke, S.E., Bose, S., Cronin, T., Klarlund, J., Chawla, A., Czech, M.P., Lambright, D.G.(2000) Structural Basis of 3-Phosphoinositide Recognition by Pleckstrin Homology Domains.  Molecular Cell 6: 385-394. PMID: 10983985.

3. Jiang, Z., Zhou, Q.L., Coleman, K.A., Chouinard, M., Bose, A., Czech, M.P.(2003) Insulin Signaling Through Akt/PKB Analyzed by siRNA-mediated Gene Silencing. Proc Natl Acad Sci U S A, 100(13):7569-7564. PMC164627.

Identification of lipid droplet proteins and mechanisms of lipid storage. A focal point of our lab over many years has been the mechanisms that control triglyceride storage in adipocytes and their relationships to insulin resistance. We discovered a family of Cide-domain containing proteins is associated with lipid droplets in adipocytes and hepatocytes, and regulate lipid storage and turnover in these metabolic cell types. Gene deletion of Cidec/FSP27 and Cidea in mice has corroborated their key roles in lipid metabolism and whole body energy expenditure, and a human subject with a disrupting mutation in CIDEC displays lipodystrophy, insulin resistance and type 2 diabetes. We also found evidence that decreased lipid droplet protein expression in  human  adipose  tissue  may  correlate  with  the  appearance  of  insulin  resistance,  consistent  with  the hypothesis that they help sequester neutral lipids within adipocytes to protect other tissues from lipotoxicity. We continue to identify pathways of triglyceride storage and release, for example the HIG2 pathway in 2015, and their relationships to systemic glucose tolerance and insulin sensitivity. This current work includes de novo fatty acid synthesis in adipocytes, and recent data shows this pathway may regulate white adipose tissue “browning” through regulation of UCP1 and other “Beige” adipocyte genes.

1. Puri V, Konda S, Ranjit S, Aouadi M, Chawla A, Chouinard M, Chakladar A, Czech MP. (2007) Fat- specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. J Biol Chem. 282(47):34213-8. PMID: 17884815.

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 very 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 now 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.

Signaling by the lipogenesis pathway through Acetyl CoA: A major function of adipocytes is to store calories as triglyceride, in part through the process of fatty acid synthesis (lipogenesis). This metabolic pathway involves a number of metabolites including Acetyl CoA, which is also a substrate for acetylation reactions that modify proteins such as histones. Thus metabolic flux through adipocyte lipogenesis may also function as a signaling pathway to the nucleus to modulate transcription via levels of Acetyl CoA that accumulate during this process. This rotation project is designed to test this idea at the molecular level by monitoring histone acetylations and resultant transcriptional events during changes in Acetyl CoA levels caused by altering physiological conditions such as exercise, obesity and diabetes. If this concept is correct, the project could lead to developing therapeutic strategies for metabolic disease based on targeting lipogenic enzymes.

Mentoring

The Czech laboratory is active in mentoring graduate students and postdoctoral fellows.  Many former student and postdoctoral trainees of the Czech laboratory are now internationally recognized professors at major universities and medical schools. These former lab members 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 Medical School

Silvia Corvera, Professor of Molecular Medicine, Co-Director of the MD/PhD Program, UMASS 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 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 Medical School

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