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.
Kryvalap Y., Jiang M. L., Kryvalap N, Hendrickson C. and Czyzyk J. SerpinB13 antibodies promote b-cell development and resistance to type 1 diabetes. Science Translational Medicine 13: eabf1587, 2021.
Lo C.-W., Kryvalap Y., Sheu T.-J., Chang C.-H. and Czyzyk J. Cellular proliferation in mouse and human pancreatic islets is regulated by serpin B13 inhibition and downstream targeting of E-cadherin by cathepsin L. Diabetologia 62: 822-834, 2019.
Kryvalap Y., Chi-Wen Lo, Manuylova K., Baldizhar R, Salazar S., Okroj D., Jospe N., and Czyzyk J. 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.
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.
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