פרופ' חגית אלדר-פינקלמן

Professor, Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University

Chair, Sackler Committee for Ph.D. Graduate Studies

Our research is focused on the molecular mechanisms regulating the protein kinase GSK-3 and their implications in human disease. GSK-3 is a central player in diabetes, neurodegenerative and psychiatric disorders, and recently emerged as a promising drug discovery target. We propose that inhibition of GSK-3 should produce therapeutic benefits in treating these disorders. We develop selective substrate competitive GSK-3 inhibitors and evaluate their efficacy and therapeutic effects in relevant in vitro and in vivo systems. So far we could show that our leading compound inhibitors had therapeutic efficacy in CNS disorders models for Alzheimer’s disease, mood disorders, and multiple sclerosis.

In recent work we identified the lysosome as a GSK-3 target. This implicated GSK-3 as a key player in protein degradation pathways, particularly autophagy ad endocytosis. Research methods combine cell biology, molecular biology and biochemistry disciplines together with bioinformatics and computational biology.

Recent Publications

Watson, RL Spalding, AC, Zielske, PS, Morgan, M, Kim, AC Guido Bommer, T, Eldar-Finkelman, H, Giordano, T, Fearon, ER, Hammer, GD, Lawrence, TS and Ben-Josef, E. 2010, GSK3β and β-catenin modulate radiation cytotoxicity in pancreatic cancer. Neoplasia. 12, 357-365.

Leng, S., Zhang, W., Zheng, Y., Liberman, Z., Rhodes, C.J., Eldar-Finkelman, H., and Sun, X.J. 2010, GSK-3β mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. J Endocrinol. 206, 171-181.

Karyo, R., Eskira, Y., Pinhasov, A., Belmaker, R., Agam, G., and Eldar-Finkelman, H. 2010, Identification of eukaryotic elongation factor-2 as a novel cellular target of lithium and GSK-3. Mol Cell Neurosci. 45, 449-455.

Shruster, A., Eldar-Finkelman, H., Melamed, E., Offen, D. 2011, Wnt signaling pathway overcomes the disruption of neurogenesis induced by oligomeric amyloid ß-peptide. J Neurochem. 116: 552-559.

Azoulay-Alfaguter, I. Yaffe, Y., Licht-Murava, A., Urbanska, M., Jaworski, J., Pietrokovski, S., Hirschberg, K. and Eldar-Finkelman, H. 2011, Distinct molecular regulation of GSK-3β controlled by it N-terminal region. Functional role in calcium/calpain signaling. J Biol Chem. 286:13470-13480.

Licht-Murava, A., Plotkin, B., Eisenstein, M., Eldar-Finkelman, H. 2011, Elucidating substrate and Inhibitor binding sites on the surface of GSK-3b and the refinement of a competitive inhibitor. J Mol Biol. 408:366-378.

Tsaadon Alon, L., Pietrokovski, S., Barkan, S., Avrahami, L. Kaidanovich-Beilin, O., Woodgett, J. Barnea, A., Eldar-Finkelman, H. 2011, Selective loss of GSK-3β in birds reveals distinct roles for GSK-3 Isozymes in tau phosphorylation. FEBS Lett. 585:1158-1162.

Monte, LM, Kramer, T. Boländer, A. Plotkin, B., Eldar-Finkelman, H., Fuertes, A., Dominguez, D., Schmidt, B. 2011, Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: an fast and atom efficient access to 1-aryl-3-benzylureas. Bioorg Med Chem Lett. 21:5610-5615.

Monte, LM, Kramer, T., Gu, J., Anumala, R. Marinelli, L., La Pietra, V., Novellino, E., Franco, B., Demedts, D., van Leuven, F., Fuertes, A., Dominguez, JM., Plotkin, B., Eldar-Finkelman, H., Schmidt, B. 2012, Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-3α. J Med Chem. 55:4407-4424.

Monte, LM, Kramer, T., Gu, J., Brodecht, M., Fuertes, Dominguez, JM., Plotkin, B., Eldar-Finkelman, H., Schmidt, B. 2013, Structure-based optimization of oxadiazole-based GSK-3 inhibitors. Eur J Med Chem. 61:26-40.

Avrahami, L., Farfara, D., Shaham-Kol, M., Vassar, R., Frenkel, D., Eldar-Finkelman, H. 2013, Inhibition of GSK-3 ameliorates b-amyloid (A) pathology and restores lysosomal acidification and mtor activity in the alzheimer’s disease mouse model. In vivo and In vitro studies. J Biol Chem 288:1295-1306.

Beurel, E., Kaidanovich-Beilin, O., Yeh, W., Song, L, Palomo, V., Michalek, SM., Woodgett, JR, Harrington, LE, Eldar-Finkelman, H., Martinez, A., Jope, RS. 2013, Regulation of Th1 cells and experimental autoimmune encephalomyelitis (EAE) by GSK-3. J. Immunol. 190:5000-5011.

La Pietra V., La Regina, G., Coluccia, A., Famiglini. V., Pelliccia, S., Plotkin, B., Eldar-Finkelman, H., Brancale, A., Ballatore, C., Crowe, A., Brunden, KR., Marinelli, L,, Novellino, E., Silvestri R. 2013. Design, synthesis, and biological evaluation of 1-Phenylpyrazolo[3,4-e]pyrrolo[3,4-g]indolizine-4,6(1H,5H)-diones as new glycogen synthase kinase-3β inhibitors. J. Med Chem. 56: 10066-10078.

Azoulay-Alfaguter I, Elya R, Avrahami L, Katz A, Eldar-Finkelman H. 2014, Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cells growth. Oncogene. In press.

Reviews

Eldar-Finkelman, H., Licht-Murava, A., Pietrokovski, S. Eisenstein, M. Substrate competitive GSK-3 Inhibitors - Strategy and Implications. 2010, Biochim Biophys Acta. 180: 598-603.

Eldar-Finkelman, H., Martinez, A. GSK-3 inhibitors: preclinical and clinical focus on CNS. 2011. Front Mol Neurosci. 4:32.

Avrahami, L., Eldar-Finkelman, H. 2013, GSK-3 and lysosomes meet in Alzheimer’s disease. Comm Integrat Biology. 6:e251789.

Azoulay-Alfaguter I, Elya R, Avrahami L, Katz A, Eldar-Finkelman H. 2014, Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cells growth. Oncogene. 34:4613-23.

Azoulay-Alfaguter I, Elya R, Avrahami L, Katz A, Eldar-Finkelman H. (2014) Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cells growth. Oncogene. 34: 4613-4623.

Aloni, E., Shapira, M., Eldar-Finkelman, H., Barnea, A. (2015) GSK-3β inhibition affects singing behavior and neurogenesis in adult songbirds. Brain, Behavior and Evolution, 85:233-244.

Klionsky, D.J., Eldar-Finkelman,H., et al (2016) Guidelines for the use and interpretation for assay for monitoring autophagy. Autophagy, 12:1-222. 

Grieco, S.F., Velmeshev, D., Magistri, M., Eldar-Finkelman, H., Faghihi, M., Jope, R.S., Beurel, E. (2016) Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3. World J. Biol. Phsyc. In press