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  • Prof.  David Lichtstein
Prof. David Lichtstein
 
Field of Study
 
Regulation of ion transport across the plasma membrane:
The primary focus of the research in my laboratory is the regulation of ion transport across the plasma membrane of eukaryotic cells. In particular, we study the main transport system for sodium and potassium, the sodium-potassium-ATPase, and its regulation by cardiac steroids.
 
Specific areas of interest:
Identification of endogenous cardiac steroids in mammalian tissue; The biological consequences of the interaction of cardiac steroids with the sodium-potassium-ATPase; Biosynthesis of the cardiac steroids in the adrenal gland; Effects of endogenous sodium-potassium-ATPase inhibitors on cell differentiation; Determination of the levels of endogenous sodium-potassium-ATPase inhibitors in pathological states, including hypertension, preeclampsia; malignancies (cancer) and manic depressive illnesses; Involvement of the sodium-potassium--ATPase/cardiac steroids system in depressive disorders; Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function; Involvement of intestinal signals in the regulation of phosphate homeostasis; Volume regulation and its involvement in the mitogenic response.
 
Cardiac Steroids and the Na+, K+-ATPase and Cardiac Steroids
Cardiac steroids, such as ouabain, digoxin and bufalin are hormones synthesized by and released from the adrenal gland and the hypothalamus. These compounds, the structure of which resembles that of plant and amphibian and butterfly steroids, interact only with the plasma membrane Na+, K+-ATPase (Figure 1). This interaction elicits numerous specific biological responses affecting the function of cells and organs.
 
Topics Currently under investigation include
Involvement of the sodium-potassium--ATPase/cardiac steroids system in depressive disorders
Depressive disorders, including major depression, dysthymia and bipolar disorder, are a serious and devastating group of diseases that have a major impact on the patients’ quality of life, and pose a significant concern for public health. The etiology of depressive disorders remains unclear. The Monoaminergic Hypothesis, suggesting that alterations in monoamine metabolism in the brain are responsible for the etiology of depressive disorders, is now recognized as insufficient to explain by itself the complex etiology of these diseases. Data from our and other laboratories has provided initial evidence that endogenous cardiac steroids and their only established receptor, the Na+, K+-ATPase, are involved in the mechanism underlining depressive disorders, and BD in particular. Our study (Biol. Psychiatry. 60:491-499, 2006) has proven that Na+, K+-ATPase and DLC are involved in depressive disorders particularly in manic-depression. We have also shown that specific genetic alterations in the Na+, K+-ATPase α isoforms are associated with bipolar disorders (Biol. Psychiatry, 65:985-991, 2009). Our recent study in this project (Eur. Neuropsychopharmacol. 22:72-729, 2012) showed that drugs affecting the Na+, K+-ATPase/cardiac steroids system are beneficial for the treatment of depression. Hence our work is in accordance to the proposition that mal functioning of the Na+, K+-ATPase/cardiac steroids system may be involved in manifestation of depressive disorders and identify new compounds as potential drug for the treatment of these maladies.
Involvement of the sodium-potassium-ATPase/cardiac steroids system in cardiac function
The classical and best documented effect of cardiac steroids, as their name implies, is to increase the force of contraction of heart muscle. Indeed, cardiac steroids were widely used in Western and Eastern clinical practices for the treatment of heart failure and atrial fibrillation. Despite extensive research, the mechanism underlying cardiac steroids actions have not been fully elucidated. The dogmatic explanation for cardiac steroids-induced increase in heart contractility is that the inhibition of Na+, K+-ATPase by the steroids causes an increase in intracellular Na+ which, in turn, attenuates the Na+/Ca++ exchange, resulting in an increased intracellular Ca++ concentration, and hence greater contractility. However, recent observations led to the hypothesis that the ability of cardiac steroids to modulate a number of intracellular signaling processes may be responsible for both short- and long-term changes in CS action on cardiac function. We are addressing this hypothesis using the zebrafish model and our ability to quantify heart function in-vivo. Heart contractility measurements were performed using a series of software tools for the analysis of high-speed video microscopic images, allowing the determination of ventricular heart diameter and perimeter during both diastole and systole. The ejection fraction (EF) and fractional area changes (FAC) were calculated from these measurements, providing two independent parameters of heart contractility (see attached movie bellow). We are currently testing the effect of cardiac steroids in the presence and absence of intracellular signaling pathways (MAP, AKT, IP3R) inhibitors. Reduction in the steroids ability to increase the force of contraction will serve as the first evidence, in-vivo, for the participation of the signaling processes in the molecular mechanisms responsible for teh action of cardiac steroids on heart muscle.  
 
Get Microsoft SilverlightMy Movie4_3.wmv
 
  
 
Laboratory Techniques  
We employ a broad range of preparations and techniques. These include isolated organs (arterial rings, smooth and cardiac muscle strips) and isolated nerve endings, as well as primary and established tissue-cultured cells. Our studies involve the application of biochemical and immunological techniques (transport and enzymatic activity measurements, RIA, ELISA), molecular biological techniques (e.g., Western and Northern blotting, and PCR), protein purification (HPLC), cellular techniques muscle contractility, cell proliferation and differentiation' in-vivo measurements of heart contractility and blood flow in Zebrafish and behavior measurements in rodents.
 
  
Biography 
Education
1970   
B.Sc. in Physiology and Zoology, The Hebrew University, Jerusalem, Israel
1970-1972   M.Sc. in Physiology, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
1973-1977  
 
 
Ph.D., Department of Physiology, Hebrew University Hadassah Medical School, Jerusalem, Israel. (Thesis: "Increased Production of Gamma Aminobutyryl choline in Cerebral Cortex Caused by Afferent Electrical Stimulation" (Thesis Advisors: Prof. J. Dobkin and Prof. J. Magnes).
1977-1979  
 
Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A.
 
 
Positions held
1970-1972
 
Teaching and Research Assistant, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1972-1974   Assistant Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1975-1977   Instructor, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1977-1979 
 
Postdoctoral Fellow, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, U.S.A.
1979-1983
 
Lecturer, (REVSON fellowship) Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
1981 (summer)
 
Visiting Scientist, Department of Physiological Chemistry and Pharmacology, Roche Institute of Molecular Biology, Nutley, New Jersey, USA
1983-1987 Senior Lecturer, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
1985-1986  
 
Visiting Scientist, Laboratory of Theoretical and Physical Biology, NICHD, National Institutes of Health, Bethesda, Maryland, USA
1988-1994   Associate Professor, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
1994-present Professor of Physiology, Department of Physiology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
1997-1998   Visiting Scientist, Laboratory of Mechanisms of Ocular Diseases, NEI, National Institutes of Health, Bethesda, Maryland, USA
2007 (summer)
 
Visiting Professor, Department of Physiology, Pharmacology, Metabolism and cardiovascular Sciences, Medical Center University of Toledo, Toledo, Ohio, USA
2007-2011 Jacob Gitlin Chair in Physiology, The Hebrew University, Jerusalem, Israel
​2011-present ​Walter & Greta Stiel Chair in Heart Studies, The Hebrew University, Jerusalem
 
Professional Membership
1979-present   International Society of Neurochemistry
1979-present   Israel Society for Physiological and Pharmacological
1980-present Society of Neurosciences (Europe)
1986-present   The American Society of Hypertension
1992-present   Israeli Society for Neurosciences
1999-present   The American Physiological Society
   
Editorial Tasks
Serving as a Reviewer for the scientific journals:
American Journal of Hypertension Journal of Neural Transmission
American Journal of Physiology Journal of Neurochemistry
Apoptosis Journal of Pharmacology and Experimental Therapeutics
Biochemical and Biophysical Research Communications Life Sciences
Basic Journal of Physiology and Pharmacology NANO
Brain Research Neurochemistry International
Bioconjugate Chemistry Neuroscience
Cell Calcium Neurotoxicity Research
Clinical Science Pathophysiology
Endocrinology Physiology and Behavior
European Neuropsychopharmacology PNAS
General and Comparative Endocrinology Psychiatry Research
Hypertension Translational Research
Journal of Cell Sciences
 
University and Other Activities
1982-1985 Chairman of the Neurobiology Teaching Division, The Hebrew University, Jerusalem
1988-1994 Elected representative of the Senior Lecturers and Associate Professors for the University Senate
1989-1997 Member of the admission committee of the Medical School, The Hebrew University, Jerusalem
1990-1996 Member of the Committee for cellular biology of the graduate studies, The Hebrew University, Jerusalem
1992-1996 Member of the Teaching Committee, Faculty of Medicine, The Hebrew University, Jerusalem
1992-1996
Chairman, Department of Physiology, The Hebrew University, Hadassah Medical School, Jerusalem
1994-1997 Member of the Committee for graduate studies, The Hebrew University, Jerusalem
1992-2002
 
Member of the Management Committee of The Institute for Medical Sciences, Faculty of Medicine, The Hebrew University, Jerusalem
1996-1999
President of the Israel Society for Physiology and Pharmacology
1998- 2002 Chairman, Institute of Medical Sciences, The Hebrew University, Hadassah Medical School, Jerusalem
1999-2002   Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem
2007–Present  Elected representative of the Professors for the executive University Senate
2008-2012 Member of the Planning and Development Committee of the Faculty of Medicine, The Hebrew University, Jerusalem
2008-2012 Chairman, Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School, Jerusalem
2009 - Present Elected member of the Senate to the Executive Committee of the Hebrew University
    
 
Current Lab Members  
Dr. Hagit Cohen-Ben Ami
Research Assistant
Moran Dvela
PhD Student
Nahum Buzaglo
PhD Student
Anastasia Singalevich
MSc Student
 
Jussi Leinonen, PhD Student 
together with Dr. Ronen Beeri 
Alon Parsai
MSc Student 
Shiri Taron
MSc Student
Oren Biro, MD Student 
together with Dr. Rena Cooper
  
 Alumni:
 
Sylvia Kachalsky Dahlia Minc‑Golomb Aline Bourrit Tamar Babila Sarah Samuelov
MSc 1982‑1985 M.Sc 1983‑1985 Ph.D. 1981‑1985 Ph.D. 1984‑1989 Ph.D. 1986‑1993
(together with Prof. H. Atlan) (together with Prof. J. Deutsch)
 
 
Chagit Bachar Eitan Haver Sharon Fruman Simona Decapua Paula Garfunkel
M.Sc 1990‑1993 Ph.D. 1989‑1996 M.Sc 1993-1996 M.Sc 1993-1996 M.Sc 1994-1996
(together with Prof. J. Deutsch)
Yoram Weil Talia Levi
Gill Almog
Jang Hyun-Gyung Gila Elchanati
M.D 1994-1996 M.Sc 1995-1998 M.D 1995-1997 Ph.D. 1995-2000 Ph.D. 1995-2001
(together with Prof. J. Deutsch) (together with H. Atlan and I. Ringel)
Ana Landsman Uri Shpolanski Nili Solomon Heidrun Weidemann Uri Shpolansky
Ph.D. 1997-2003 M.Sc. 1999-2001 M.Sc 2000-2002 Post Doc. 2000-2001 Ph.D. 2002-2010
(together with Prof. A. Ilani) (together with Prof. Hananni)
Salach Dahar Bela Ziv Linda Gutman Inbal Goldstein Reuma Mordechai
M.D. 2003-2004 M.Sc. 2003- 2005 M.Sc. 2003- 2005 Ph.D. 2003- 2010 M.Sc. 2005- 2007
Maoz Nesher Orit Salomon Yehuda Schwarz
Ph.D. 2005- 2011 M.Sc. 2005-2007 M.D. 2006-2007
 
  
Collaborating Investigators
 
Prof. J. Deutsch, Dept. Pharmaceutical Chemistry, School of Pharmacy, Hebrew University​
Prof. A. Ilani, Dept. of Medical Neurobiology, The Hebrew University-Hadassah Medical School ​
Prof. H. Rosen, Dept. of Microbiology and Molecular Genetics, IMRIC, The Hebrew University-Hadassah Medical School​
Prof. Amir Askari, Department of Physiology and Pharmacology, College of Medicine, University of Toledo, Toledo, Ohio, USA​
Dr. Reena Cooper, Department of Psychiatry, The Hebrew University-Hadassah Medical School
Dr. Ronen Beeri, Department of Cardiology, The Hebrew University-Hadassah Medical School
 
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