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Faculty Profile

Rhoda E. Hirsch, Ph.D.

Dr. Rhoda E. Hirsch

Professor, Department of Medicine (Hematology)

Professor, Department of Anatomy & Structural Biology

 

Professional Interests

The further understanding of hemoglobin structure, function, and stability has become paramount in the search for therapies directed towards highly morbid or fatal hemoglobinopathies (diseases that arise from mutant hemoglobins) that continue to be a world-wide health problem. Hemoglobin instability leads to a variety of red blood cell (RBC) consequences, unique to the particular hemoglobinopathy. β6 hemoglobin mutants form aggregates in the RBC: Why does oxy HbC (β6 Glu → Lys) form crystals in the red blood cell in contrast to deoxy sickle cell hemoglobin [HbS, β6 Glu → Val] that forms polymers? Interactions of hemoglobin with natural or synthetic allosteric effectors and RBC components are providing key information about (1) intramolecular pathways of communication in hemoglobin; and (2) critical regions imparting unique stability to hemoglobin molecules important for the development of hemoglobin based oxygen carriers (i.e., blood substitutes). Unique hemoglobins with unusual stability, such as the giant hemoglobin (a dodecamer, 3.8 x 106 Da) found in the earthworm, Lumbricus terrestris provide insight into some of these questions. Hemoglobin conformational alterations that lead to instability are being pursued by site-specific steady-state and time-resolved spectroscopy, crystallography, molecular dynamics, and crystal growth studies.

A recent focus of our laboratory is the hemoglobinopathy HbE (β26 Glu →Lys) and its related diseases. HbE is the most common hemoglobin mutant world-wide and is predominantly found in SE Asia. With the increasing wave of immigration to N. America, HbE is now the second most common hemoglobinopathy found in the USA, second to sickle cell hemoglobin. The consequence of this mutation is very different from that of the β6 mutants. In vitro, HbE is highly unstable. Surprisingly, HbE homozygous individuals present a benign clinical picture, while double heterozygotes such as HbE/β-thalassemia present severe clinical symptoms in this life-threatening disease. The mechanistic role of HbE as the origin of the pathophysiology is yet to be determined. We have established transgenic mouse models of HbE hemoglobinopathies to be correlated with biophysical studies (crystallography, spectroscopy) in order to determine molecular mechanisms that give rise to the specific pathophysiology. We have recently discovered that HbE is reduced in function as a nitrite reductase that would result in less nitric oxide production, a compound critical for cardiovasculature physiology.

While aiming to create RBC models derived from cord blood stem cells and from human embryonic stem cells (hESC), we have identified functional primary cilia in hESC. An on-going project aims to determine its role in modulating hESC differentiation/proliferation as regulated by signal transduction mechanisms.

 

Selected Publications

Exemplary References 

NCBI PubMed search of "R.E. Hirsch"

  1. QY Chen, ME Fabry, AC Rybicki, SM Suzuka, TC Balazs,  Z Etzion, K de Jong, EK Akoto, JE Canterino, DK Kaul, FA Kuypers, D Lefer, EE Bouhassira, and Rhoda Elison Hirsch. “A transgenic mouse model expressing exclusively human hemoglobin E: indications of a mild oxidative stress.”  Blood Cells, Molecules and Disease 48:91-101 (2012)
  2.  CJ Roche, V Malashkevich, TC Balazs, D Dantsker, QY Chen, J Moreira, SC Almo, JM Friedman, and RE Hirsch.  “Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E: Implications for Production of Bioactive Nitric Oxide”. Journal of Biological Chemistry 286: 23452-23466 (2011).
  3. J Canterino, O Galkin, PG Vekilov, and RE Hirsch, “ Phase Separation and Crystallization of Hemoglobin C in Transgenic Mouse and Human Erythrocytes.”  Biophysical Journal, in press (2008).
  4. E Kiprilov, A Awan, R Desprat, M Velho, CA Clement, AG Byskov, CY Andersen, ST Christensen, P Satir, EE Bouhassira, and RE Hirsch. “Human Embryonic Stem Cells in Culture Possess Primary Cilia with Hedgehog Signaling Machinery.”  Journal of Cell Biology  180:897-904 (2008)
  5. JP Harrington, S Kobayashi, SC Dorman, SL Zito, and RE Hirsch.  “Acellular Invertebrate Hemoglobins as Model Therapeutic Oxygen Carriers: Unique Redox Potentials.” Artificial Cells, Blood Substitutes and Biotechnology 35:53-67 (2007) 
  6. QY Chen, TC Balazs, RL Nagel, RE Hirsch.  Human and mouse hemoglobin association with the transgenic mouse erythrocyte membrane. FEBS Letters 580:4485-4490 (2006).
  7. E Olivier, C Qiu, M Velho, RE Hirsch, EE Bouhassira.  Large-scale production of embryonic red blood cells from human embryonic stem cells. Experimental Hematology 34:1635-1642 (2006)
  8. Qy Chen and RE Hirsch. A Direct and Simultaneous Detection of Zinc Protoporphyrin IX, Free Protoporphyrin IX, and Fluorescent Heme Degradation Product in Red Blood Cell Hemolysates. Free Radical Research 40:285-294 (2006)
  9. QY Chen, I Lalezari, RL Nagel, and RE Hirsch. “Liganded Hemoglobin Structural Perturbations by the Allosteric Effector L35.” Biophysical Journal 88:2057-2067 (2005).
  10. LN Patskovska, YV Patskovsky, SC Almo, and RE Hirsch. “COHbC and COHbS Crystallize in the R2 Quaternary State at Neutral pH in the Presence of PEG 4000.” Acta Crystallographica D61: 566-573 (2005).
  11. QY Chen, EE Bouhassira, A Besse, S M Suzuka, ME Fabry, RL Nagel, and RE Hirsch. “Generation of Transgenic Mice Expressing Human Hemoglobin E.”  Blood Cells, Molecules, and Diseases 33:303-307 (2004).
  12. QY Chen, PG Vekilov, RL Nagel, and RE Hirsch. “Liquid-Liquid Phase Separation in Hemoglobins: Distinct Aggregation Mechanisms of the b6 Mutants. Biophysical Journal.  86:1702-1712 (2004).  
  13. C Fablet, QY Chen, V Baudin-Creuza, MC Marden, RL Nagel, J Pagnier, and RE Hirsch. “b132K Salt Bridge and Sickle Hemoglobin Stability and Conformation.”  British Journal of Haematology 122:317-325 (2003)
  14. RE Hirsch, “Hemoglobin Fluorescence.” Methods in Hemoglobin Disorders Molecular Medicine), pp. 133-154, Humana Press, New Jersey (2003)
 
 

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Contact

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 925
Bronx, NY 10461

Tel: 718.430.3604
rhoda.hirsch@einstein.yu.edu

 
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