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Kinase Inhibition and Nanotechnology for Diabetes (KIND) research group

Group Leader: Dr. Anna Czarna 
E-mail: anna1.czarna@uj.edu.pl

 

 

 

 

 

 

 

 

 
 
Team members:
Dr. Barbara Pucelik  Post-doc
Dr. Katarzyna Pustelny Post-doc
Alex Matsuda  Senior Technician
PhD students:
Agata Barzowska PhD
Przemysław Grygier PhD
Marco Turchetto -Erasmus student
and masters and bachelor students.
 
Research themes:
 
Over the past decades, we have seen significant changes in lifestyle (i.e., diet, physical activity, and microbial exposure) that contribute to the increasing prevalence of overweight and obesity worldwide. Consequently, this leads to numerous complications and severe conditions closely related to the metabolic imbalance that is diabetes, with cardiovascular disease, neurodegenerative disorders, liver steatosis and cancer. Currently, diabetes is divided into two main types: type 1 diabetes (T1D) and type 2 diabetes (T2D). Patients with T1D have a dramatic decrease in the number of beta cells (β-cells) in the pancreas, resulting in impaired insulin secretion and hyperglycemia. In the second disease model (T2D), insulin resistance causes a compensatory expansion of β-cells and a dangerous increase in plasma insulin levels. It is worth mentioning that most genes associated with T2D type regulate the mass and/or function of pancreatic secretory cells. Novel therapeutic approaches involve attempts to increase functional pancreatic secretory cell mass in place of burdensome insulin supplementation. Thus, diabetes is now a chronic disease requiring lifelong maintenance treatment. Natural and long-term regeneration of β-cell mass resulting in an actual cure of diabetes is an important milestone we all look forward to. Regenerative medicine is now entering the canon of scientific research and clinical practice. Our work builds on previous discoveries in protein structural biology, low molecular weight inhibitors, and human organoids derived from induced pluripotent stem cells (iPSCs) to understand the mechanisms of regeneration of pancreatic endocrine cell fractions. Research has shown that certain kinases, including the dual-specific tyrosine kinase DYRK1A and the β isoform of glycogen synthase kinase 3 (GSK3β) inhibit the proliferation and activity of pancreatic β cells. Given the complexity of the disease mechanism, it is unlikely to be caused by a single factor. Therefore, a thorough understanding of the molecular mechanisms of the components that regulate cellular processes is essential. The main indication of our research is the development of specific inhibitors to sustainably improve β-cell function. In our work we use state-of-the-art cell models for in vitro studies, including isolated human pancreatic islands as well as laboratory animal models (mice). Careful experimental planning supported by in-depth expertise, combined with extensive international and interdepartmental academic collaboration and support from the clinical sector, will significantly contribute to the smooth implementation of this project. Our proposed research strategy involves the acquisition of new tools in anti-diabetic therapy. The expected outcome of the projects will be the confirmation of the effectiveness of the developed low molecular weight inhibitors for growth stimulation of transplanted β-cells and maintenance of the population of these cells in the living organism. In the long term, the proposed strategies offer the vision of developing therapeutic models to cure diabetes completely (in place of current insulin supplementation), resulting in improved quality of life for millions of people and significant relief for health care systems worldwide.
 
 
Research Collaborations:
1. South China University of Technology, Guangzhou, China
2. Perpha Pharmaceuticals, Roscoff, France
3. Helmholtz Zentrum Muenchen, Germany
4. Institute for Medicinal Chemistry, Leibniz University of Hanover, Germany
5. Arctic University of Norway, Tromso, Norway
6. Dana Farber Cancer Institute, Boston, US
7. Medical University of Warsaw, Warsaw, Poland
8. Faculty of ChemistryJU, Krakow, Poland
 
Research Projects:
1. SONATA BIS‐9; Restoration of beta-cell function via inhibition of diabetic kinome; 2020-2024
2. Consortium: H2020‐JTI‐IMI2‐2020‐21‐single‐stage as a partner scientist; Corona Accelerated R&D in Europe; 2020-2025
3. NAWA Polish National Agency for Academic Exchange NAWA; Novel approaches for diabetes management by a combination of inhibition of DYRK1A kinase and stem cells application.; 2010-2023
4. NAWA; Bilateral exchange of scientists between the Republic of Poland and the Republic of India; 2021-2022
5. BioS - Minigranty we współpracy; Deconvolution of the molecular target(s) of AC27 compound by chemical proteomics approach for innovative antidiabetic drug development; 2021-2023
 
Research papers:
 
Barzowska A, Pucelik B, Pustelny K, Matsuda A, Martyniak A, Stępniewski J, Maksymiuk A, Dawidowski M, Rothweiler U, Dulak J, Dubin G, Czarna A. DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis. Cells. 2021; 10(9):2263. IF: t.b.a.
Pucelik B, Barzowska A, Dąbrowski JM, Czarna A. Diabetic Kinome Inhibitors - A New Opportunity for β-Cells Restoration. International Journal of Molecular Sciences. 2021;22(16):9083. IF: t.b.a.
Napolitano V, Dabrowska A, Schorpp K, Mourão A, Barreto-Duran E, Benedyk M, Botwina P, Brandner S, Bostock M, Chykunova Y, Czarna A, Dubin G, Fröhlich T, Hoelscher M, Jedrysik M, Matsuda A, Owczarek K, Pachota M, Plettenburg O, Potempa J, Rothenaigner I, Schlauderer F, Szczepanski A, Mohn KG, Blomberg B, Sattler M, Hadian K, Popowicz GM, Pyrc K. Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses. bioRxiv preprint. 2021 Mar 21. No IF.
Xu CF, Chen GJ, Luo YL, Zhang Y, Zhao G, Lu ZD, Czarna A, Gu Z, Wang J. Rational designs of in vivo CRISPR-Cas delivery systems. Advanced Drug Delivery Reviews. 2021 Jan;168:3-29. IF: 13.300.
Wang Y, Luo YL, Chen YF, Lu ZD, Wang Y, Czarna A, Shen S, Xu CF and Wang J. Dually regulating the proliferation and the immune microenvironment of melanoma via nanoparticle-delivered siRNA targeting onco-immunologic CD155. Biomaterials Science. 2020 Dec 7;8(23):6683-6694. IF: 6.183.
Luo Y-L, Liang L-F, Gan Y-J, Liu J, Zhang Y, Fan Y-N, Zhao G, Czarna A, Lu Z-D, Du X-J, Shen S, Xu C-F, Lian Z-X and Jun Wang. An All-in-One Nanomedicine Consisting of CRISPR-Cas9 and an Autoantigen Peptide for Restoring Specific Immune Tolerance. ACS Applied Materials & Interfaces. 2020, 12, 43, 48259-48271. doi: 10.1021/acsami.0c10885. IF: 8.758.
Wang F, Zhang H, Chen W, Czarna A, Yang B, Wang Y. Function of C-terminal peptides on enzymatic and interfacial adsorption properties of lipase from Gibberella zeae. Biochimica et Biophysica Acta - General Subjects. 2018 Dec;1862(12):2623-2631. IF: 3.422.
Czarna A, Wang J, Zelencov D, Liu Y, Deng X, Choi HG, Zhang T, Zhou W, Chang JW, Kildalsen H, Seternes OM, Gray NS, Engh RA, Rothweiler U. Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors. Journal of Medicinal Chemistry. 2018 Sep 13;61(17):7560-7572. IF: 6.205.
Czarna A, Sanada F, Matsuda A, Kim J, Signore S, Pereira JD, Sorrentino A, Kannappan R, Cannata A, Hosoda T, Rota M, Crea F, Anversa P, Leri A. Single-cell analysis of the fate of c-kit-positive bone marrow cells. NPJ Regenerative Medicine. 2017;2:27. Corresponding author. IF: 7.021.
Kannappan R, Matsuda A, Ferreira-Martins J, Zhang E, Palano G, Czarna A, Cabral-Da-Silva MC, Bastos-Carvalho A, Sanada F, Ide N, Rota M, Blasco MA, Serrano M, Anversa P, Leri A. p53 modulates the fate of cardiac progenitor cells ex vivo and in the diabetic heart in vivo. EBioMedicine. 2017;16:224-237. IF: 5.736.
Pustelny K, Zdzalik M, Stach N, Stec-Niemczyk J, Cichon P, Czarna A, Popowicz G, Mak P, Drag M, Salvesen GS, Wladyka B, Potempa J, Dubin A, Dubin G. Staphylococcal splb serine protease utilizes a novel molecular mechanism of activation. The Journal of Biological Chemistry. 2014;289:15544-15553. IF: 4.238.
Sanada F, Kim J, Czarna A, Chan NY, Signore S, Ogorek B, Isobe K, Wybieralska E, Borghetti G, Pesapane A, Sorrentino A, Mangano E, Cappetta D, Mangiaracina C, Ricciardi M, Cimini M, Ifedigbo E, Perrella MA, Goichberg P, Choi AM, Kajstura J, Hosoda T, Rota M, Anversa P, Leri A. C-kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circulation Research. 2014;114:41-55. IF: 14.467.
Czarna A, Berndt A, Singh HR, Grudziecki A, Ladurner AG, Timinszky G, Kramer A, Wolf E. Structures of drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function. Cell. 2013;153:1394-1405. IF: 38.637.
Czarna A, Breitkreuz H, Mahrenholz CC, Arens J, Strauss HM, Wolf E. Quantitative analyses of cryptochrome-mBMAL1 interactions: Mechanistic insights into the transcriptional regulation of the mammalian circadian clock. The Journal of Biological Chemistry. 2011;286:22414-22425. IF: 4.238.
Czarna A, Beck B, Srivastava S, Popowicz GM, Wolf S, Huang Y, Bista M, Holak TA, Domling A. Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists. Angewandte Chemie. 2010;49:5352-5356. IF: 12.959.
Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Dömling A, Holak TA. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle. 2010;9:1104–1111. IF: 3.699.
Srivastava S, Beck B, Wang W, Czarna A, Holak TA, Domling A. Rapid and efficient hydrophilicity tuning of p53/Mdm2 antagonists. Journal of Combinatorial Chemistry. 2009;11:631-639. IF: 3.381.
Czarna A, Popowicz GM, Pecak A, Wolf S, Dubin G, Holak TA. High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx. Cell Cycle. 2009;8:1176-1184. IF: 3.699.
Rothweiler U, Czarna A, Weber L, Popowicz GM, Brongel K, Kowalska K, Orth M, Stemmann O, Holak TA. NMR screening for lead compounds using tryptophan-mutated proteins. Journal of Medicinal Chemistry. 2008:51: 5035-5042. IF: 6.336.
Popowicz GM, Czarna A, Holak TA. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle. 2008;7:2441-2443. IF: 3.699.
Rothweiler U, Czarna A, Krajewski M, Ciombor J, Kalinski C, Khazak V, Ross G, Skobeleva N, Weber L, Holak TA. Isoquinolin-1-one inhibitors of the mdm2-p53 interaction. ChemMedChem. 2008;3:1118-1128. IF: 3.204.
Dubin G, Stec-Niemczyk J, Kisielewska M, Pustelny K, Popowicz GM, Bista M, Kantyka T, Boulware KT, Stennicke HR, Czarna A, Phopaisarn M, Daugherty PS, Thogersen IB, Enghild JJ, Thornberry N, Dubin A, Potempa J. Enzymatic activity of the staphylococcus aureus splb serine protease is induced by substrates containing the sequence trp-glu-leu-gln. Journal of Molecular Biology. 2008;379:343-356. IF: 4.787.
Popowicz GM, Czarna A, Rothweiler U, Szwagierczak A, Krajewski M, Weber L, Holak TA. Molecular basis for the inhibition of p53 by Mdmx. Cell Cycle. 2007;6:2386-2392. IF: 3.699.
Popowicz GM, Dubin G, Stec-Niemczyk J, Czarna A, Dubin A, Potempa J, Holak TA. Functional and structural characterization of Spl proteases from staphylococcus aureus. Journal of Molecular Biology. 2006;358:270-279. IF: 4.787.