ד"ר איזבל צויבל

סגל אקדמי קליני ברפואה פנימית
רפואה פנימית סגל אקדמי קליני
ד"ר איזבל צויבל

מחקר

המעבדה שלנו חוקרת מחלות כבד, כולל מחלות כבד מטבוליות המלוות השמנת יתר. התסמונת המטבולית היא מגפה הולכת ועולה באולם המערבי. אחת מהתופעות   של התסמונת המטבולית  היא התפתחות של כבד שומני, שיכול להתקדם לכבד שומני דלקתי, כבד עם שחמת ו סרטן הכבד. אנחנו חוקרים מעורבות של מולקולות ספציפיות שמשפיעות על תהליכים אלו.

בנוסף אנחנו מעוניינים לפענח מנגנונים מעורבים בשחמת הכבד  הנגרמת ע"י פגיעות בדרכי מרה. למחלות של דרכי מרה בבני אדם אין עדיין טיפול , מלבד השתלת כבד, לכן הבנה של התהליכים במחלות אלו שיכולים להוביל לטיפולים חדשים היא חשובה ביותר.

 

 

Our lab is researching various aspects of liver disease. One of the symptoms of the metabolic syndrome, which has become a growing epidemic in the Western world, is fatty liver. Fatty liver can advance to steatohepatitis, fibrosis cirrhosis and ultimately hepatocellular carcinoma. We are investigated several molecules that control the development of fatty liver disease and insulin resistance in diet-induced obesity.

In addition, we study cholestatic liver diseases, diseases that involve injury to bile ducts and lead to fibrosis and cirrhosis. In human patients, there are no drugs so far for treatment of these diseases and the only option is liver transplantation.  We are investigating various molecules that regulate inflammation and fibrosis in cholestatic liver diseases, which may lead to new therapies.

EDUCATION, ACADEMIC EXPERIENCE AND ACADEMIC AWARDS

EDUCATION

1975-1978: The Hebrew University, Jerusalem, Israel, Biology, B.Sc. 1978.

1980-1982: The Hebrew University, Hadassah Medical School, Jerusalem, Israel Immunology, M.Sc. 1982.

1982-1986: Weizmann Institute of Science, Rehovot, Israel. Cell Biology, Ph.D 1987.

ACADEMIC AND PROFESSIONAL EXPERIENCE

1987-1989: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Post-Doctoral Fellow.

1989-1994: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Associate.

1995-present: The Research Center for Digestive Tract and Liver Diseases,

Tel Aviv Sourasky Medical Center, Principal Investigator.

2012-present Senior lecturer, Sackler school of Medicine, Tel Aviv University  

ACADEMIC AND PROFESSIONAL AWARDS

1998-2000: Ministry of Health. The role of liver extracellular matrix in colon cancer metastasis to the liver.  

12000-2003: The Israeli Science Foundation.The role of erb-B2 in colon cancer metastasis to the liver: regulation by liver extracellular matrix.

2000-2002: The Israeli Cancer Research Foundation.  The role of syndecans 2 and 4 in colorectal tumor progression.

2002-2005: Ministry of Health. Mechanisms of anoikis in hepatocytes.

2003-2006: Consortium Magnet for Cell Therapy (Bereshit). Isolation, characterization and proliferation of hepatocyte progenitors from human cord blood,

2009-2013: The Israeli Science Foundation. Mechanisms of thyroid hormones activation of hepatic stellate cells via increased expression of p75 neurotrophin receptor and activation of Rho.

2012: Weizmann-Sourasky grant. Role of sortilin in sphingolipid metabolism during high fat diet- induced hepatic steatosis and insulin resistance.

2019-2023: The Israeli Science Foundation. Deciphering the role of sortilin, IL-6 and leukemia inhibitory factor signaling in the ductular reaction following cholestatic liver injury.      

תחומי מחקר

מחלות כבד מטבוליות ומחלות כבד של דרכי המרה

פירסומים

ORIGINAL ARTICLES

  1. Zvibel I, Raz A. 1985. Establishment and characterization of a new BALB/c angiosarcoma tumor system. Int. J. Cancer 36: 261-272.
  2. Raz A, Meromsky L, Zvibel I, Lotan R. 1987. Transformation-related changes in the expression of endogenous cell lectins. Int. J. Cancer 39: 353-360.
  3. Doerr R, Zvibel I, Chiuten D, D’Olimpio J, Reid LM. 1989. Clonal growth of tumors on tissue-specific biomatrices and correlation with organ site specificity of metastases. Cancer Res. 49: 384-392.
  4. Zvibel I, Halay E, Reid LM. 1991. Heparin/hormonal regulation of autocrine growth factor mRNA synthesis and abundance: Relevance to clonal growth of tumors. Mol. & Cell. Biol. 11: 108-116.
  5. Kraft A, Reid LM, Zvibel I. 1993. Suramin inhibits growth yet promotes IGF II expression in HepG2 cells. Cancer Res. 53: 652-657.
  6. Sigal SH, Brill S, Reid LM, Zvibel I, Gupta S, Hixson D, Faris R, Holst P. 1994. Characterization and enrichment of fetal rat hepatoblasts by immunoadsorbtion (“panning”) and fluorescence activated cell sorting. Hepatology 19: 999-1006.
  7. Zvibel I, Brill S, Reid LM. 1995. Insulin-like growth factor II regulation of gene expression in rat and human hepatomas. J. Cell. Physiol. 162: 36-43.
  8. Brill S, Zvibel I, Reid LM. 1995. Maturation-dependent changes in the regulation of liver-specific gene expression in embryonal versus adult primary liver cultures. Differentiation 59: 95-102.
  9. Fiorino AS, Zvibel I. 1996. Disruption of cell-cell adhesion in the presence of sodium butyrate activates the 92kD collagenase in MDCK cells. Cell. Biol. International 20: 489-500.
  10. Zvibel I, Halpern Z, Papa M. 1998. Extracellular matrix modulates the expression of growth factors and growth factor receptors in liver-colonizing colon cell lines. Int. J. Cancer 77: 295-301.
  11. Zvibel I, Fiorino AS, Brill S, Reid LM. 1998. Phenotypic characterization of hepatoma cell lines and lineage-specific regulation of gene expression by differentiation agents. Differentiation 63: 215-223.
  12. Zvibel I, Brill S, Halpern Z, Papa MZ. 1998. Hepatocyte extracellular matrix modulates expression of growth factors and growth factor receptors in human colon cancer cells. Exp. Cell. Res. 245: 123-131.
  13. Brill S, Zvibel I, Reid LM. 1999. Expansion conditions for early hepatic progenitor cells from embryonal and neonatal rat livers. Dig. Dis. Sci. 44: 364-371.
  14. Zvibel I, Brill S, Halpern Z, Papa M. 1999. Amphiregulin and hepatocyte-derived extracellular matrix regulate proliferation and autocrine growth factor expression in colon cancer cell lines of varying liver-colonizing capability. J. Cell. Biochem. 76:332-340.
  15. Zvibel I, Brill S, Papa M, Halpern Z. 2000. Hepatocyte-derived soluble factors regulate proliferation and autocrine growth factor expression in colon cancer cell lines of varying liver-colonizing capability. Tumor Biol. 21: 187-196.
  16. Zvibel I, Brill S, Halpern Z, Moskovitz S, Yayon A, Papa M. 2001. Soluble and matrix associated heparan sulfate proteoglycans increase expression of erb-B2 and erb-B3 in colon cancer cell lines. Int. J. Cancer 91: 316-321.
  17. Zvibel I, Papa M, Halpern Z, Brill S. 2001. Synergies of heparin and second messenger pathways involved in tissue-specific gene expression in hepatocytes. Dig. Dis. Sci. 46: 1039-1045.
  18. Kouniavsky G, Khaikin M, Zvibel I, Zippel D, Brill S, Halpern Z, Papa M. 2002. Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. Clin. Exp. Metastasis 19: 55-60.
  19. Brill S, Zvibel I, Papa M, Halpern Z, Oren R. 2002. The role of fetal and adult hepatocyte extracellular matrix in the regulation of tissue-specific gene expression in fetal and adult hepatocytes. Eur. J. Cell Biol. 81: 43-50.
  20. Fishman S, Brill S, Papa MZ, Halpern  Z, Zvibel I. 2002. Heparin derived-disaccharides modulate proliferation and erb-B2-mediated signal transduction in colon cancer cell lines. Int. J. Cancer 99: 179-184.
  21. Gur E, Deckel R, Zvibel I, Brazovsky E, Kariv R, Brill S, Halpern Z, Oren R. 2003. A novel method for liver repopulation: Hetero grafting of micro-liver slices in a rat model. Liver Transplantation 9: 421-424.
  22. Kariv R, Enden A, Zvibel I, Rosner G, Brill S, Halpern Z, Oren R. 2003. Triiothyronine and interleukin 6 (IL-6) induce expression of HGF in an immortalized hepatic stellate cell line. Liver International 23:187-193.
  23. Dekel R, Zvibel I, Brill S, Brazovsky E, Goldberg I, Halpern Z, Oren R. 2003. Gliotoxin ameliorates development of fibrosis and cirrhosis in a thioacetamide rat model. Dig. Dis. Sci.  48:1642-1647.
  24. Zvibel I, Brill S, Kariv R, Traister A, Golan T, Chebath J, Halpern Z, Revel M, Oren R. 2004. The chimeric molecule IL-6/soluble IL-6 receptor is a potent mitogen for fetal hepatocytes. J. Cell. Physiol. 200: 245-252.
  25. Traister A, Breitman I, Bar-Lev  E, Zvibel I, Harel A, Halpern Z, Oren R. 2005. Nicotinamide induces apoptosis and reduces collagen I and proinflammatory cytokines expression in rat hepatic stellate cells. Scand. J. Gastroenterology. 40:1226-1234.
  26. Oren R, Breitman I, Gur E, Traister A , Zvibel I, Brazovsky E, Shafritz DA,  Halpern Z. 2005. Whole fetal liver transplantation-a new approach to cell therapy.  Liver Transplantation 11: 929-933.
  27. Zvibel I, Bronstein M, Hubel E, Bar-Lev E, Halpern Z, Oren R. 2006. Isolation, characterization and culture of Thy1-positive cells from fetal rat livers. World. J. Gastroenterology 12: 3841-3847.
  28. Bruck R, Weiss S, Traister A, Zvibel I, Aeed H, Halpern Z, Oren R. 2007. Induced-hypothyroidism accelerates the regression of liver cirrhosis in rats. J. Gastroenterol & Hepatol 22:2189-2194.
  29. Zvibel I, Bar-Zohar D, Kloog Y, Oren R, Reif S. 2008. The effect of Ras inhibition on the proliferation, apoptosis and matrix metalloproteases activity in rat hepatic stellate cells. Dig. Dis. Sci 53:1048-1053.
  30. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, Webb M, Zvibel I, Goldiner I, Blendis L, Halpern Z, Oren R.2008. Role of leisure-time physical activity in nonalcoholic fatty liver disease: A population-based study. Hepatology   48: 1791-8.
  31. Bruck R, Weiss S, Aeed H, Pines M, Halpern Z,  Zvibel I. 2009. Additive inhibitory effect of experimentally-induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor γ and retinoic acid receptor. Dig. Dis. Sci. 54:292-9.
  32. Zvibel I, Halfon P, Fishman S, Penaranda G, Leshno M, Bet Or A, Halpern Z, Oren R. 2009. Syndecan 1 (CD138) serum levels: a novel biomarker in predicting liver fibrosis stage in patients with hepatitis C. Liver International 29: 208-12.
  33.  Zvibel I, Atias D, Phillips A, Halpern Z, Oren R. 2010.Thyroid hormones induce activation of primary rat hepatic stellate cells via increased expression of p75 neurotrophin receptor and direct activation of Rho. Lab Invest 90:674-84.
  34. Ben Shlomo S, Zvibel I, Oren R, Fishman S. 2011. Glucagon-Like Peptide-1 reduces hepatic lipogenesis via activation of AMP-activated Protein Kinase. J. Hepatol 54:1214-23.
  35. Ben-Shlomo S, Einstein FH, Zvibel I, Atias D, Shlomai A, Halpern Z, Barzilai N, Fishman S. 2012. Perinephric and epididymal fat affect hepatic metabolism in rats. Obesity 20:151-6.
  36. Zelber-Sagi S, Ratziu V, Zvibel I, Goldiner I, Blendis L, Morali G, Halpern Z, Oren R. 2012. The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease-induced liver injury: a study in the general population. Eur J Gastroenterol Hepatol. 24: 262-9.
  37. Zvibel I, Wagner A, Pasmanik-Chor M, Varol C, Oron-Karni V, Santo EM, Halpern Z, Kariv R.2013. Transcriptional profiling identifies genes induced by hepatocyte-derived extracellular matrix in metastatic human colorectal cancer cell lines. Clin Exp Metastasis 30:189-200.
  38. Ben Shlomo S, Zvibel I, Rabinowich L, Goldiner I, Shlomai A, Santo EM, Halpern Z, Oren R, Fishman S. 2013. Dipeptidyl peptidase 4-deficient rats have improved bile secretory function in high fat diet-induced steatosis. Dig Dis Sci 58:172-8.
  39. Ben Shlomo S, Zvibel I ,Varol C, Spektor  L, Shlomai A, Santo EM, Halpern Z, Fishman S. 2013.Reduced adipose tissue inflammation in dipeptidyl peptidase 4 deficient rats may involve glucose-dependent insulinotropic polypeptide. Obesity 21:2331-41.
  40. Khatib M*,  Zvibel I*, Zelber-Sagi S, Varol C, Lahat G, Abu-Abeid S, Klausner JM, Halpern Z, Fishman S. 2014.Discriminatory metabolic and inflammatory parameters in serum and omental adipose tissue of obese patients with different insulin sensitivity. J Clin & Translational Endocrinol. 1, 115-119. * equal authors.
  41. Varol C*,  Zvibel I*, Spektor L, Mantelmacher FD, Vugman M, Tamar T, Khatib M,  Elmaliah E, Halpern Z, Fishman S. 2014. Long-acting glucose–dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation. J Immunol 193:4002-9. * equal authors.
  42. Rabinowich L*, Fishman S*, Hubel E, Thurm T, Park WJ, Pewzner-Jung Y, Futerman A, Halpern Z, Zvibel I.2015. Sortilin deficiency improves the metabolic phenotype and reduces hepatic steatosis in a murine model of diet-induced obesity. J Hepatol 62:175-81.*equal authors.
  43. Hubel E, Saroha A, Park WJ, Pewzner-Jung Y, Lavoie EG, Futerman AH, Rafael Bruck, Sigal Fishman S, Dranoff JA, Shibolet O*, Zvibel I*. 2017. Sortilin deficiency reduces ductular reaction, hepatocyte apoptosis and liver fibrosis in cholestatic-induced liver injury. Am.J. Pathol. 187:122-133. * equal senior authors.
  44. Mantelmacher FD, Fishman S, Cohen K, Pasmanik Chor M, Yamada Y, Zvibel I*, Varol C*. 2017. Glucose-Dependent Insulinotropic Polypeptide Receptor Deficiency Leads to Impaired Bone Marrow Hematopoiesis. J Immunol.198:3089-3098. *equal senior authors.
  45. Erez N*, Hubel E*, Avraham R, Cohen R, Fishman S, Bantel H, Manns M, Tirosh B, Zvibel I#, Shibolet O#. 2017. Hepatic amiodarone lipotoxicity is ameliorated by genetic and pharmacological inhibition of endoplasmatic reticulum stress. # equal senior authors. Toxicol Sci. 159: 402-412.
  46. Mantelmacher FD*, Zvibel I*, Cohen K, Epshtein A, Pasmanik- Chor M, Vogl T, Kuperman Y, Weiss S, Drucker DJ, Varol C, Fishman S. 2018. GIP regulates inflammation and body weight by restraining myeloid cell-derived S100A8/A9. Nature Metab, 1.  equal authors

REVIEW ARTICLES

1. Reid LM, Zvibel I. Production of matrix-degrading enzymes determined by tumor implantation site. J. Natl. Can. Inst. 1990; 82:1866 (editorial).

2. Reid LM, Zvibel I, Watanabe T, Fujita M, Agelli M, Montgomery K, Kraft,A, and Ochs A. Cooperative regulation of gene expression in liver cells by hormones and extracellular matrix. In: Molecular Mechanisms in Cellular Growth and Differentiation, Academic Press, Inc., San Diego, CA, vol 7,pp 69-106,1990.

3. Kraft A, Zvibel I, Doerr R, Chiuten D, Ochs A, Reid LM. Matrix influences organ site specificity of metastases by regulating production and response to autocrine growth factors. In: Metastasis: Basic Research and its Clinical Applications. Contrib. Oncol. Rabes H, Peters PE, Munk K, eds, Basel, Karger, Switzerland, vol 44, pp 203-223,1992.

4. Brill S, Holst P, Sigal S, Zvibel I, Fiorino AS, Ochs A, Somasundaran U, Reid LM. Hepatic progenitor populations in embryonic,neonatal and adult liver.  Proc.Soc.Exper.Biol.Med. 204, pp 261-269, 1993.

5. Zvibel I, Mintz Y, Brill S, Halpern Z, Papa MZ. The role of the liver environment in the regulation of colon cancer metastasis. IMAJ 2000; 2, 48-51.

6. Zvibel I, Smets F, Soriano H. Anoikis: roadblock to cell transplantation? Cell Transplantation 2002; 11: 621-630.

BOOK CHAPTERS

1. Zvibel I, Kraft A. Extracellular matrix and metastasis. In: Extracellular Matrix: its Chemistry, Biology and Pathobiology, David van Thiel, editor in chief , Marcel Dekker, N.Y., 559-579,  1993.

2. Brill S, Holst P, Zvibel I, Fiorino AS, Sigal S, Somasundaran U, Reid LM. Extracellular matrix regulation of growth and gene expression in liver cell lineages and hepatomas. In: The Liver Biology and Pathobiology, 3rd ed., Arias et al, eds, Raven Press, N.Y., vol 44, pp 869-898, 1994.

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