Jan Czyzyk, MD

Associate Professor, Department of Laboratory Medicine and Pathology

Jan Czyzyk

Contact Info

jczyzyk@umn.edu

Office Phone 612-273-3495

Office Address:
C587 Mayo Memorial Bldg.
420 Delaware St SE
Minneapolis, MN 55455

Mailing Address:
MMC 76 Mayo
8076A (Campus Delivery Code)
420 Delaware St SE
Minneapolis, MN 55455

MD, Medical University of Warsaw, Warsaw, Poland, 1992

Residency in Anatomic Pathology, Yale-New Haven Hospital, New Haven, CT, 1996-1998

Fellowship in Renal Pathology, Yale-New Haven Hospital, CT, 1998-2000

Postdoctoral Research Fellow, University of North Carolina at Chapel Hill, Chapel Hill, NC, 1993-1996

Summary

Dr. Czyzyk is a physician-scientist with clinical expertise in the native and transplant kidney disease and basic research interests in autoimmune diseases with emphasis on Type 1 Diabetes (T1D) in recent years. Although T1D has been traditionally considered a pediatric disease, this condition can affect older individuals too, including patients over 35 years of age who develop detectable autoimmunity against pancreatic islets and relatively rapid progression to insulin dependence [latent autoimmune diabetes in adults or LADA]. Regular insulin therapy or islet transplant in certain situations are the only treatments currently available for these patients.

T1D is characterized by inflammatory destruction of small clusters of insulin producing cells called the islets of Langerhans. Czyzyk and his colleagues study how both normal function of the islets and their inflammation are regulated by islet sensing signals that are generated in the surrounding exocrine tissue - a process they believe is regulated by proteases. Czyzyk is particularly interested in how the balance between proteases and inhibitors of proteases called serpins affect inflammation and tissue regeneration of pancreatic islet cells.  Studies in Czyzyk’s laboratory suggest that an immune response to the serpin B13 protease inhibitor and the consequent increase in protease activity is unique in that it is protective during the destruction of pancreatic islets.

Protocols that enhance protease activity regulated by serpin B13 may be beneficial to diabetic patients by both suppressing islet inflammation associated with autoimmunity and by promoting regeneration of insulin-producing beta cells in the islets. One such protocol involves a specific autoantibody Czyzyk’s team has discovered that could serve as a protective biomarker. The molecule suppresses serpin B13 thereby allowing higher levels of cathepsin proteases that afford a level of protection for pancreatic islets. The autoantibody’s mechanism of action is thought to involve protease-mediated cleavage of adhesion molecules in the extracellular matrix as well as Notch signaling, which affects endocrine cellular differentiation. Once the precise mechanism is known, Czyzyk will attempt to engineer endocrine-positive pancreatic progenitor cells, which differentiate into pancreatic islet alpha or beta cells, to become active beta cells that produce insulin.

In their renal studies, Czyzyk and colleagues have focused on serum response factor (SRF) and podocytes, highly specialized cells of the kidney glomerulus that help regulate glomerular filtration. SRF is a master regulator of the actin cytoskeleton. Transcriptomic studies have shown that altered SRF expression may play a role in human kidney disease. The researchers found that SRF and two of its co-factors are vital for maintaining the structure and function of podocytes. Cultured podocytes with reduced SRF expression exhibit defects in the actin cytoskeleton and dysregulated expression of the MKL1 and MKL2 genes and perhaps others necessary for a functional actin cytoskeleton. Such defects disrupt podocyte structural development and normal renal function. Ongoing research is aimed at revealing target genes essential for podocyte homeostasis.

Awards & Recognition

2016 Winning access to the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) biosamples, NIDDK Central Repository of Non-Renewable Samples

2014 Reviewer for the grants under the Innovation and Technology Support Programme of the Hong Kong Government

2014- Member of the TrialNet Biomarkers and Mechanism Review Panel

2013-2016 Collaboration with TrialNet – an international network of researchers working on type 1 diabetes

2010-2012 Collaboration with the Belgian Diabetes Registry - the major center in studies for the cure of type 1 diabetes in Europe

2009-2010 Diabetes Endocrinology Research Center Grant

2009 Reviewer to Diabetes, PlosOne, and Cardiovascular Diabetology

2005-2009 American Cancer Society Research Scholar Grant

2004-2005 Medical School’s Pilot Grant in Translational & Interdisciplinary Research

2002-2004 Young Investigator Award, National Kidney Foundation

2000-2003 KO8 Clinical Investigator Award, NIH/NIAID

1992 Top prize-winner of the “Primus inter Pares” contest, Gold Award

1986 Summa Cum Laude Graduate, Zamoyski Secondary School

Research

Publications

Kryvalap Y. and Czyzyk J., Neogenesis of insulin-producing cells is heavily influenced by serpin B13 and its protease targets. In preparation.

Lo C.-W., Kryvalap Y. and Czyzyk J., Cathepsin L mediates anti-serpin B13 induced replicative activity in pancreatic beta cells. In preparation.

Guo B., Lyu Q., Silvano O. J., Dirkx R., Christie K. C., Czyzyk J., Gharavi A. G., Small E. M., and Miano J. M., Serum response factor is essential for maintenance of podocyte structure and function. Journal of the American Society of Nephrology 2018 Feb;29(2):416-422. doi: 10.1681/ASN.2017050473.

Kryvalap Y., Chi-Wen Lo, Manuylova K., Baldizhar R, Salazar S., Okroj D., Jospe N., Czyzyk J. and Type 1 Diabetes TrialNet Study Group. Antibody response to serpin B13 induces regeneration in mouse pancreatic islets and slows down the decline in the residual beta-cell function in children with recent-onset type 1 diabetes mellitus. Journal of Biological Chemistry 291: 266-278, 2016.

Pokuri V. K, Xu B., Neppalli V., Czyzyk J., Berenji F., Holstein S. A. and McCarthy P. L., Synchronous presentation of monoclonal gammopathy and Fabry nephropathy; diagnostic renal biopsy obviates initiation of myeloma therapy. Annals of Hematology 94: 1067-1068, 2015.

Baldzizhar R., Fedorchuk C., Jha M., Henegariu O. and Czyzyk J., Anti-serpin antibody-mediated regulation of proteases in autoimmune diabetes. Journal of Biological Chemistry 288: 1612-1619, 2013.

Szepietowska B., Zhu W., Czyzyk J., Eid T. and Sherwin R.S. EphA5-ephrinA5 interaction within the ventromedial hypothalamus influences counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia. Diabetes 62: 1282-1288, 2013.

Czyzyk J., Henegariu O., Preston-Hurlburt P., Baldzizhar R., Fedorchuk C., Esplugles E, Gorus F. K., Bottomly K., Herold K. and Flavell R. A. Enhanced anti-serpin antibody activity inhibits autoimmune inflammation in type 1 diabetes. Journal of Immunology 188: 6319-6327, 2012.

Ma H., Togawa A., Soda K., Zhang J., Lee S., Ma M., Yu Z., Ardito T., Czyzyk J., Diggs L., Joly D., Hatakeyama S., Kawahara E., Holzman L., Guan J. L. and Ishibe S., Inhibition of podocyte FAK protects against proteinuria and foot process effacement. Journal of American Society of Nephrology 21: 1145-1156, 2010. 

Czyzyk J.*, Chen H.-C., Bottomly K. and Flavell R. A., p21Ras/Impedes Mitogenic signal Propagation regulates cytokine production and migration in CD4 T cells. Journal of Biological Chemistry 283: 23004-23015, 2008.

Carrithers M. D., Carrithers L.M., Czyzyk J. and Henegariu O., Characterization of severe parenchymal phenotype of experimental autoimmune encephalomyelitis in (C57BL6xB10.PL)F1 mice. Journal of Neuroimmunology 187: 31-43, 2007.

Czyzyk J., The role of Toll-like receptors in the pathogenesis of renal diseases. Seminars in Nephrology 2006 (25th Anniversary Edition), 26: 167-172, 2006.

Marginean E., Bennick M., Czyzyk J., Robert M.E. and Jain D. Gastric Siderosis: Patterns and Significance. American Journal of Surgical Pathology 30: 514-520, 2006.

Czyzyk J., Brogdon J. L., Badaou SA., Henegariu O., Preston-Hurlburt P., Flavell R. and Bottomly, K., Activation of CD4 T cells by Raf-independent effectors of Ras. Proceedings of the National Academy of Sciences USA 100: 6003-6008, 2003.

Czyzyk J., Leitenberg D., Taylor T. and Bottomly K., Combinatorial effect of T-cell receptor ligation and CD45 isoform expression on the signaling contribution of the small GTPases Ras and Rap1. Molecular and Cellular Biology 20: 8740-8747, 2000.

Clinical

Board Certifications

Board Certified in Anatomic Pathology