PRODUCTION OF BIOACTIVE NO: ORIGIN OF HEMOGLOBIN E ASSOCIATED PATHOPHYSIOLOGY
Hirsch Rhoda
Albert Einstein Col Of Med Yeshiva Univcity: Bronx country: United States (us)
Grant 5R21HL106421-02 from National Heart, Lung, And Blood Institute
Keywords: Affinity; Anemia; base; Biological Availability; Blood Vessels; Cardiac; Cardiovascular Physiology; Cell membrane; Cessation of life; Chronic; Clinical; Coupling; Data; Databases; Disease; Erythrocytes; Evaluation; Exhibits; Functional disorder; Gel; Heart; Heart Diseases; Hemoglobin; Hemoglobin E; Hemoglobin E Disease; Hemoglobinopathies; In Vitro; Individual; Induced Mutation; innovation; Lead; Ligands; Light; Link; Mediating; Membrane; Mental Retardation; Modeling; Molecular; Molecular Conformation; Morbidity - disease rate; mutant; Mutation; Nitric Oxide; Nitrite Reductase; Nitrites; novel; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathologic; Pathology; Patients; Play; Production; programs; Property; protein structure; Proteins; Protocols documentation; Reaction; Reactive Oxygen Species; Relative (related person); Reporting; Resolution; Role; Series; Sickle Cell Anemia; Source; Structure; Testing; Thalassemia; Therapeutic; therapy development; X-Ray Crystallography
Relevance: Layman Summary This proposal aims to understand the fundamental causes that give rise to Hemoglobin E diseases, one of which can cause body and mental retardation and can lead to death, usually from heart malfunction. It is the aim of this proposal to test the hypothesis that this disease originates from properties of HbE that reduce its capacity to produce nitric oxide from nitrite. These findings have the potential to change the way doctors view and treat the often fatal HbE/¿-thalassemia disease
Project start date: 2010-12-15
Project end date: 2012-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R21HL106421-02 (2012): $186750
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Hirsch Rhoda
PRODUCTION OF BIOACTIVE NO: ORIGIN OF HEMOGLOBIN E ASSOCIATED PATHOPHYSIOLOGY
Hirsch Rhoda
Albert Einstein Col Of Med Yeshiva Univcity: Bronx country: United States (us)
Grant 1R21HL106421-01 from National Heart, Lung, And Blood Institute
Abstract: Hemoglobin (Hb) E (2E26K) is the most common worldwide naturally occurring mutant Hb with a mutation at the 1121 interface. EE individuals exhibit a mild, chronic anemia while HbE/2-thalassemia individuals show a range of clinical manifestations, including high morbidity, and death, often resulting from cardiac dysfunction. The significant role of HbE in the red blood cell pathophysiology and molecular mechanisms giving rise to the HbE diseases is enigmatic. Since, HbE has been shown to have normal oxygen affinity (Bunn et al., 1972), we have proposed a possible mechanism whereby HbE may have reduced capacity to generate sufficient bioactive nitric oxide (NO) (1) to confer protection against high levels of membrane damaging reactive oxygen species (ROS) arising from the 2-thalassemia and (2) as a secondary NO source for endothelial functioning. In support of this hypothesis we have obtained preliminary data from HbE showing decreased nitrite reductase activity compared to HbA. Our group recently obtained the high resolution deoxy and liganded HbE structures (Protein Data Bank entries 1YVQ, 1YVT, 3DUT) and found that the tertiary conformations within the T and R quaternary structures of HbE are altered relative to HbA. The proposed project which builds on these two findings, seeks to establish the extent and molecular origins of the altered nitrite reactivity. The project will utilize innovative sol-gel encapsulation protocols to trap and characterize the reactivity of the T and R state of HbE with respect to a series of reactions proposed to contribute to the production of bioactive NO. The project seeks to determine whether the source of HbE altered reactivity to generate bioactive forms of NO from nitrite arises from changes in allostery, in local tertiary structure or in the redox properties of the T and R states. These studies are of significance in that they are likely to provide a novel mechanism for the origin of HbE-derived pathophysiology with implications for other Hb related pathologies and diseases linked to endothelial dysfunction. There is the potential for a new paradigm in which to develop therapies for HbE 2-thalassemia. This proposal aims to understand the fundamental causes that give rise to Hemoglobin E diseases, one of which can cause body and mental retardation and can lead to death, usually from heart malfunction. It is the aim of this proposal to test the hypothesis that this disease originates from properties of HbE that reduce its capacity to produce nitric oxide from nitrite. These findings have the potential to change the way doctors view and treat the often fatal HbE/2-thalassemia disease
Keywords: Active Oxygen; Affinity; Anemia; base; Bioavailability; bioavailability of drug; Biologic Availability; Biological Availability; blood corpuscles; Blood erythrocyte; Blood normocyte; Blood Vessels; Cardiac; Cardiac Diseases; Cardiac Disorders; cardiovascular function; Cardiovascular Physiology; Cell membrane; Cessation of life; Chronic; Clinical; clinical data repository; clinical data warehouse; conformation; conformational state; Coupling; Crystallography, X-Ray; Crystallography, X-Ray Diffraction; Crystallography, X-Ray/Neutron; Crystallography, Xray; Cytoplasmic Membrane; Data; Data Banks; Data Bases; data repository; Databank, Electronic; Databanks; Database, Electronic; Databases; Death; Disease; disease/disorder; Disorder; Dysfunction; Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium-Derived Relaxing Factor; Erythrocytes; Erythrocytic; Evaluation; Exhibits; Functional disorder; Gel; gene product; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Hb SS disease; HbSS disease; Heart; Heart Diseases; heart disorder; heavy metal lead; heavy metal Pb; Hemoglobin; Hemoglobin E; Hemoglobin E Disease; Hemoglobin S Disease; Hemoglobin sickle cell disease; Hemoglobin sickle cell disorder; Hemoglobinopathies; Hemoglobinopathies / Iron Metabolism; In Vitro; Individual; Induced DNA Alteration; Induced Mutation; Induced Sequence Alteration; innovate; innovation; innovative; intervention development; Lead; Ligands; Light; Link; Marrow erythrocyte; Mediating; Membrane; membrane structure; Mental Retardation; Modeling; Molecular; Molecular Configuration; Molecular Conformation; Molecular Stereochemistry; Mononitrogen Monoxide; Morbidity; Morbidity - disease rate; mutant; Mutation; Nitric Oxide; Nitric Oxide, Endothelium-Derived; Nitrite Reductase; Nitrites; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; novel; O element; O2 element; Outcome; oxidation reduction reaction; Oxidation-Reduction; Oxidative Stress; Oxygen; Oxygen Radicals; Pathologic; Pathology; pathophysiology; Patients; Pb element; Photoradiation; Physiologic Availability; Physiopathology; Plasma Membrane; plasmalemma; Play; Pro-Oxidants; Production; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; protein structure; Proteins; Protocol; Protocols documentation; public health relevance; Reaction; Reactive Oxygen Species; Red Blood Cells; Red blood corpuscule; Red Cell; Red cell of marrow; Redox; relational database; Relative; Relative (related person); Reporting; Resolution; Reticuloendothelial System, Erythrocytes; Role; Series; Sickle Cell Anemia; sickle cell disease; sickle disease; sicklemia; Single Crystal Diffraction; social role; Source; Structure; Testing; Thalassemia; Therapeutic; therapy development; treatment development; vascular; X Ray Crystallographies; X-Ray Crystallography
Relevance: Layman Summary This proposal aims to understand the fundamental causes that give rise to Hemoglobin E diseases, one of which can cause body and mental retardation and can lead to death, usually from heart malfunction. It is the aim of this proposal to test the hypothesis that this disease originates from properties of HbE that reduce its capacity to produce nitric oxide from nitrite. These findings have the potential to change the way doctors view and treat the often fatal HbE/¿-thalassemia disease
Project start date: 2010-12-15
Project end date: 2012-11-30
Budget start date: 15-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-10-069
1R21HL106421-01 (2011): $249000