Liya Wang

Disputerad i medicinsk och fysiologisk kemi vid SLU januari 1997.

Docent i medicinsk biokemi sedan 2003.

Nuvarande anställning är universitetslektor i veterinärmedicinsk biokemi.

Undervisar i grundutbildningskurser för veterinär, husdjurs agronom, djursjukskötare, m.m. i ämne biokemi och cell biologi.

Forskar om enzymer i nukleotidmetabolism.

Undervisar i följande kurser:

Biomedicinsk baskurs kurskod VM0110 (Kursledare och lärare i biokemi och cell biologi) -veterinärprogrammet

Organ struktur och funktion kurskod VM0111 (lärare i blodets kemi) - veterinärprogrammet

Djurens biologi 1 kurskod HV0120 (delkursansvarig, lärare i biokemi) – agronomprogrammet- husdjur, etologi och djurskydd, kadidatprogrammet - sport och sällskapsdjur

Djurens biologi 2 kurskod HV0133 (delkursansvarig, lärare i cell biologi) - agronomprogrammet- husdjur, etologi och djurskydd, och sport och sällskapsdjur

Djurens anatomi och fysiologi kurskod DO0086 (lärare i biokemi)- djursjukskötare programmet

My research is focused on enzymes in nucleotide metabolism of human, animal and bacterial origin on medical, biochemical and molecular aspects and can be divided into: mitochondrial deoxynucleoside kinases in inherited and acquired mitochondrial diseases, oxidative stress induced protein modifications; deoxynucleotide (dNTP) pool imbalance in mitochondrial diseases; enzymes in Mycoplasma nucleotide biosynthesis as targets for antibiotic development. Currently we are focusing on the following projects:

1. Enzymes in nucleotide metabolism in health and diseases

Deoxynucleoside triphosphates (dNTPs) are the building blocks of DNA and are essential for life. dNTPs are synthesized by two distinct pathways i.e. the de novo and the salvage pathways. The de novo pathway begins with amino acids, CO2, ATP, etc. and is mainly active in proliferating cells. The salvage pathway is the reuse of nucleobases and nucleosides to make nucleotides, which plays an important role in maintain adequate dNTPs for nuclear DNA and mitochondrial DNA (mtDNA) synthesis and repair. Deoxynucleoside kinases are the rate limiting enzymes in salvage of deoxynucleosides. In mammalian cells there are four deoxynucleoside kinases e.g. cytosolic thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK), and mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK).

   We have done lots of work with these enzymes over the last 25 years and contributed to elucidation of mechanism of mtDNA depletion and deletion diseases caused by TK2 or dGK deficiency and also the design of therapeutic approach for patients with mtDNA depletion and deletions diseases. Our recent work has contributed to the understanding of the role of mitochondrial dNTP synthesis in mitochondrial function and in inherited and acquired mitochondrial diseases, and mitochondrial toxicity of anticancer and antiviral nucleoside analogs. In line with our study it was shown recently that manipulation of dNTP pools could be used to eradicate cancer cells.

    In the study of causal relationship of cellular dNTP pool imbalance and mitochondrial diseases, I am collaborating with Prof. Anu Soumalainen Wartiovaara, University of Helsinki, Finland, Dr. Mario Ost, German Institute of Human Nutrition, and Dr. Antonella Spinazzola, MRC Mill Hill Laboratory, London, UK, who are leading scientists in the field of mitochondrial disorders/diseases. Using mouse models of mitochondrial diseases caused by mutations in genes coding enzymes of mitochondrial DNA (mtDNA) replication and mitochondrial maintenance, we have found that mitochondrial diseases remodel multiple cellular metabolic pathways including glucose, amino acids and one carbon cycle that resulted in alterations in nucleotide metabolism and imbalanced dNTP pools, which in turn accelerate mitochondrial dysfunction.

I collaborate also with Dr. Jörgen Bierau, Inborn Errors of Metabolism, Department Clinical Genetics, Holland, to study the consequences of mutations in the thymidylate kinase gene found in microcephalic patient. We are studying the causal relationship of TMPK mutation in microcephaly using cultured fibroblast cells derived from patients, and also to find the alternative pathway for thymidylate biosynthesis that compensates the lack of thymidylate kinase. We have one Ph.D student working on this project.

   Thymidine kinase 1 (TK1) is a cytosolic enzyme and expressed only in rapidly proliferating cells such as cancer cells. TK1 is also present in serum from patients with various cancers and other infections, which make it a useful marker for cancer diagnosis. However, up to date the mechanism of TK1 excretion is still not known, and that’s why we are aiming at examining the molecular mechanism of TK1 excretion using cultured cancer cells as model in a Ph.D project.

2. Serum TK1 as a biomarker for veterinary cancer management.

Cancer is the primary cause of death in older dogs. The prevalence of cancer is high particularly in bitches with an annual incidence of 272 per 100,000 female dogs and 99 in male dogs. The current available diagnostic procedures are not sufficient and there is a large need to improve, particularly blood test, that can aid cancer diagnosis and prognosis. I have been involved in the studies of canine and feline TK1 with the aim to find a useful biomarker for veterinary medicine, and have shown that serum TK1 activity is elevated in dogs with malignant diseases (cancers) and also bacterial infection (pyometra). Since January 2017 we provide service for veterinarians cross the country to measure serum TK activity in dogs with suspected cancerous disease to aid in diagnosis and disease monitoring.

Development of an ELISA for TK1 as biomarker is an ongoing project using polyclonal anti dog TK1 antibodies and a monoclonal anti human TK1 antibody. The results, recently published in PloS One, are the first definite proof that TK1 protein determinations provide valuable information concerning prognosis and early detection of disease both in hematologic and solid tumors in dogs. Our aim is to establish a robust ELISA kit suitable for routine clinical use and large-scale production. Our team members’ competence in basic science, clinical practice and business development should ensure the establishment and commercialization of this TK1 ELISA kit for veterinary medicine. We will extend this research to other animal species e.g. cat and horse as well. We are collaborating with Professor Henrik Rönnberg, and VMD Sara Saellström, at the Department of Clinical Science, SLU, and a research group in Switzerland, and Alertix Veterinary diagnostic AB on this project.

Har handlett ett antal master uppsatser för studenter från båda SLU och UU

har varit huvud handledare för 3 doktorander och beträdandehandledare för 4 dotorander.

Nuvarande huvudhandledare åt en doktorand

Selected Publications (2013-2017):

1. Nahid A. Khan, Joni Nikkanen, Shuichi Yatsuga, Liya Wang, Christopher Jackson1, Riikka Kivelä, Andrea Ballabio, Vidya Velagapudi, Anu Suomalainen (2017) mTORC1 regulates mitochondrial stress response in mitochondrial myopathy progression. Cell Metabolism 26:419-428

2. Brita Ardesjö-Lundgren, Katarina Tengvall, Kerstin Bergvall, Fabiana HG Farias, Liya Wang, Åke Hedhammar, Kerstin Lindblad-Toh, and Göran Andersson. (2017) Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs. Vet. Dermatol. 28:377-e88 (Doi:10.1111/vde. 12441)

3. Ilaria Dalla Rosa, Yolanda Cámara, Romina Durigon, Chloe Moss, Sara Vidoni, Gokhan Akman, Lilian Hunt, Mark Johnson, Sarah Grocott, Liya Wang, David R. Thorburn, Michio Hirano, Joanna Poulton, Robert W. Taylor, Greg Elgar, Ramon Martí, Peter Voshol, Ian J. Holt & Antonella Spinazzola (2016) MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. PloS Genetics 12(1):e1005779.

4. Joni Nikkanen, Saara Forsström, Liliya Euro, Ilse Paetau, Rebecca Kohnz, Liya Wang, Dmitri Chilov, Jenni Viinamäki, Anne Roivainen, Päivi Marjamäki, Sofia Ahola, Jana Buzkova, Mügen Terzioglu, Nahid A Khan, Anders Paetau, Tuula Lönnqvist, Antti Sajantila, Pirjo Isohanni, Henna Tyynismaa, Daniel Nomura, Brendan Battersby, Vidya Velagapudi, Christopher Carroll, Anu Suomalainen (2016). Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools And Remodel One-Carbon Metabolism. Cell Metabolism 23:1-14. (http://dx.doi.org/10.1016/j.cmet.2016.01.019)

5. Liya Wang (2016) Mitochondrial purine and pyrimidine metabolism and beyond. Nucleoside, Nucleotide and Nucleic Acid. 35:578-594 (Doi:10.1080/15257770.2015.1125001)

6. Iulia Karlsson, Ragnvi Hagman, Anders Johanisson, Liya Wang, Fredrik Södersten, and Sara Wernersson (2016) Serum KC-like chemokine concentrations are significantly increased in canine bacterial sepsis. Veterinary Immunology and Immunopathology 170:41-46 (doi:10.1016/j.vetimm.2016.01.005)

7. Iulia Karlsson, Ragnvi Hagman, Youzhi Guo, Patrice Humblot, Liya Wang, Sara Wernersson. (2015) Pathogenic Escherichia coli and lipopolysaccharide enhance the expression of IL-8, CXCL5, and CXCL10 in canine endometrial stromal cells. Theriohenology. 84:34-42.

8. Huang, Rui; Yap, Li-Peng; Wang, Liya; Kouhi, Aida; Conti, Peter; Chen, Kai. (2015) Development of biological assays for screening thymidine analogues as potent and selective PET probes of human thymidine kinases. J. Nucl. Med. 56 (3):

9. Ren Sun and Liya Wang (2014) Thymidine kinase 2 enzyme kinetics elucidates the mechanism of thymidine induced mitochondrial DNA depletion. Biochemistry 53:6142-6150

10. Ren Sun, Staffan Eriksson, Liya Wang (2014) Zidovudine induces down-regulation of mitochondrial deoxynucleoside kinases: implications for mitochondrial toxicity of antiviral nucleoside analogs. Antimicrobial Agents and Chemotherapy. 58:6758-6766

11. Ren Sun, Staffan Eriksson, Liya Wang (2014) Down-regulation of mitochondrial thymidine kinase 2 and deoxyguanosine kinase by didanosine: Implication for mitochondrial toxicities of anti-HIV nucleoside analogs. Biochem Biophys Res Comm. 450:1021-1026

12. Ming-Hsiang Lee, Liya Wang and Zee-Fen Chang (2014) The contribution of mitochondrial thymidylate synthesis in preventing the nuclear genome stress. Nucleic Acid Research, 42:4972-4984

13. Wang L, Schmidl S and Stülke J (2014) Mycoplasma pneumoniae thymidine phosphorylase. Nucleoside, Nucleotides & Nucleic acids. 33:296-304

14. Sun R, Eriksson S and Wang L (2014) Mitochondrial thymidine kinase 2 but not deoxyguanosine kinase is up-regulated during stationary growth phase of the cultured cells. Nucleoside, Nucleotides & Nucleic acids. 33:282-286

15. Wojtczak BA, Olejniczak AB, Wang L, Eriksson S and Lesnikowiski ZL (2013) Phosphorylation of nucleoside- metallacarborane and carborane conjugates by nucleoside kinases. Nucleoside, Nucleotides & Nucleic acids.  32(10), 571-588.

16. Sun R and Wang L (2013) Inhibition of Mycoplasma pneumoniae growth by FDA-approved antiviral and anticancer nucleoside and nucleobase analogs. BMC Microbiology 13:184

17. Karlsson I, Wernersson S, Ambrosen A, Wang L, Kindahl H, Södersten F, Hagman R (2013) Increased concentrations of C-reactive protein but not high-mobility group box 1 in dogs with naturally occurring sepsis. Veterinary Immunology and Immunopathology. 156:64-72

18. Stålhandske P, Wang L, Westberg S, von Euler H, Groth E, Gustafsson SA, Eriksson S, Lennerstrand J (2013) Homogeneous assay for real-time and simultaneous detection of thymdine kinase a and deoxycytidine kinase activities. Analytical Biochemistry 432:155-164

19. Sharif H, R. Hagman, L. Wang, S. Eriksson (2013) Elevation of serum thymidine kinase 1 in a bacterial infection: Caine pyometra. Theriogenology. 79:17-23