Sami Fouad Noujaim

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Emotion and Affective Neuroscience

Active NIH awards

• Peptibodies As Novel Therapies in Atrial Fibrillation

  5R01HL163943-03

  NHLBI · FY 2025 · $609K

  ABSTRACT Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is rising alarmingly. It is particularly challenging to treat persistent AF and to restore normal sinus rhythm with currently available antiarrhythmics. Therefore, novel ion channel blocking modalities are needed for the development of the next generation of antiarrhythmic pharmacotherapies in persistent AF. A hallmark of remodeling in the chronically fibrillating atria is the presence of a constitutively active, parasympathetic stimulation independent acetylcholine sensitive inward rectifier potassium current (IKACh). Constitutively active IKACh acts as a background inward rectifier conductance and can contribute to the shortening of the atrial effective refractory period, and consequently to the perpetuation of AF. We demonstrated earlier that IKACh blockade with the peptidotoxin tertiapinQ, a 21-amino acid synthetic peptide blocker of IKACh originally isolated from the European honeybee venom, terminates persistent AF. We thus bioengineered, produced and characterized a novel, and potent IKACh blocking peptibody. Peptibodies are chimeras generated as fusion proteins of the fragment crystallizable (Fc) domain of the human immunoglobulin G (IgG1) with a bioactive “warhead” peptide. Peptibodies combine the biologic/therapeutic activity of a given peptide, with the stability of monoclonal antibodies and are stable and safe molecules that are emerging as viable clinical therapies. Our IKACh blocking peptibody was constructed as a fusion protein between the Fc fragment of human IgG1 and tertiapinQ linked together by an octaglycine spacer. In this application, we propose to test the hypothesis that bioengineered peptibodies designed as potent and bioactive blockers of IKACh are antiarrhythmic in persistent AF. Our goals are: 1- to delineate the structural determinants for the peptibody’s block of IKACh; 2- to determine the atrial specificity, electrophysiological safety and therapeutic potential of anti-IKACh peptibodies in a pig model of persistent AF; and 3- to bioengineer next generation peptibodies that have increased IKACh potency and specificity. Successful accomplishment of our proposal should be a major step forward in the deliberate, innovative, and rational development of much needed and effective antifibrillatory agents based on bioengineering approaches that target ion channels important in the mechanism of a major cardiac disease.

• Peptibodies As Novel Therapies in Atrial Fibrillation

  5R01HL163943-02

  NHLBI · FY 2024 · $598K

  ABSTRACT Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is rising alarmingly. It is particularly challenging to treat persistent AF and to restore normal sinus rhythm with currently available antiarrhythmics. Therefore, novel ion channel blocking modalities are needed for the development of the next generation of antiarrhythmic pharmacotherapies in persistent AF. A hallmark of remodeling in the chronically fibrillating atria is the presence of a constitutively active, parasympathetic stimulation independent acetylcholine sensitive inward rectifier potassium current (IKACh). Constitutively active IKACh acts as a background inward rectifier conductance and can contribute to the shortening of the atrial effective refractory period, and consequently to the perpetuation of AF. We demonstrated earlier that IKACh blockade with the peptidotoxin tertiapinQ, a 21-amino acid synthetic peptide blocker of IKACh originally isolated from the European honeybee venom, terminates persistent AF. We thus bioengineered, produced and characterized a novel, and potent IKACh blocking peptibody. Peptibodies are chimeras generated as fusion proteins of the fragment crystallizable (Fc) domain of the human immunoglobulin G (IgG1) with a bioactive “warhead” peptide. Peptibodies combine the biologic/therapeutic activity of a given peptide, with the stability of monoclonal antibodies and are stable and safe molecules that are emerging as viable clinical therapies. Our IKACh blocking peptibody was constructed as a fusion protein between the Fc fragment of human IgG1 and tertiapinQ linked together by an octaglycine spacer. In this application, we propose to test the hypothesis that bioengineered peptibodies designed as potent and bioactive blockers of IKACh are antiarrhythmic in persistent AF. Our goals are: 1- to delineate the structural determinants for the peptibody’s block of IKACh; 2- to determine the atrial specificity, electrophysiological safety and therapeutic potential of anti-IKACh peptibodies in a pig model of persistent AF; and 3- to bioengineer next generation peptibodies that have increased IKACh potency and specificity. Successful accomplishment of our proposal should be a major step forward in the deliberate, innovative, and rational development of much needed and effective antifibrillatory agents based on bioengineering approaches that target ion channels important in the mechanism of a major cardiac disease.

• Cardiac Toxicity of Flavorings in Electronic Nicotine Delivery Systems

  5R01ES032099-05

  NIEHS · FY 2024 · $449K

  CARDIAC TOXICITY OF FLAVORINGS IN ELECTRONIC NICOTINE DELIVERY SYSTEMS Tobacco cigarette smoking is on the decline, but the usage of electronic nicotine delivery systems (ENDS) is gaining popularity, specifically in the teen and young adult age groups. While the cardiac toxicity of tobacco cigarette smoking has been widely studied and is well established, the possible cardiac toxicity of ENDS products and their design characteristics, such as added flavorings, are largely underexplored. For instance, a form of electronic nicotine delivery known as vaping, uses “e-liquid” in order to generate “e-vapor”, an inhalable smoke-like aerosolized mixture containing nicotine and flavors. Here, we propose to investigate how e-liquids with different flavors affect cardiac in-vitro and in-vivo toxicity, in cell culture and in animal models. Our hypothesis is that inhalation exposure to e-liquid flavorings increases cardiac oxidative stress, leading to electrophysiological toxicity and arrhythmogenesis. We will conduct our studies in three aims: 1)- To investigate the in-vitro cardiac harm and toxicity of e-liquid flavorings, 2)- To investigate the in-vivo cardiac harm and toxicity of e-liquid flavorings, and 3)- To investigate the role of oxidative stress in mediating the cardiac toxicity of e-liquid flavorings. We believe that this proposal will produce new, useful and focused insights into the potential in-vivo and in-vitro adverse effects of e-liquid flavorings using functional and cellular indicators of cardiac harm. Our findings will hopefully be valuable in increasing our understanding of whether the flavoring aspect of ENDS products design could cause cardiac in- vivo and in- vitro toxicities.

• Peptibodies As Novel Therapies in Atrial Fibrillation

  1R01HL163943-01A1

  NHLBI · FY 2023 · $621K

  ABSTRACT Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is rising alarmingly. It is particularly challenging to treat persistent AF and to restore normal sinus rhythm with currently available antiarrhythmics. Therefore, novel ion channel blocking modalities are needed for the development of the next generation of antiarrhythmic pharmacotherapies in persistent AF. A hallmark of remodeling in the chronically fibrillating atria is the presence of a constitutively active, parasympathetic stimulation independent acetylcholine sensitive inward rectifier potassium current (IKACh). Constitutively active IKACh acts as a background inward rectifier conductance and can contribute to the shortening of the atrial effective refractory period, and consequently to the perpetuation of AF. We demonstrated earlier that IKACh blockade with the peptidotoxin tertiapinQ, a 21-amino acid synthetic peptide blocker of IKACh originally isolated from the European honeybee venom, terminates persistent AF. We thus bioengineered, produced and characterized a novel, and potent IKACh blocking peptibody. Peptibodies are chimeras generated as fusion proteins of the fragment crystallizable (Fc) domain of the human immunoglobulin G (IgG1) with a bioactive “warhead” peptide. Peptibodies combine the biologic/therapeutic activity of a given peptide, with the stability of monoclonal antibodies and are stable and safe molecules that are emerging as viable clinical therapies. Our IKACh blocking peptibody was constructed as a fusion protein between the Fc fragment of human IgG1 and tertiapinQ linked together by an octaglycine spacer. In this application, we propose to test the hypothesis that bioengineered peptibodies designed as potent and bioactive blockers of IKACh are antiarrhythmic in persistent AF. Our goals are: 1- to delineate the structural determinants for the peptibody’s block of IKACh; 2- to determine the atrial specificity, electrophysiological safety and therapeutic potential of anti-IKACh peptibodies in a pig model of persistent AF; and 3- to bioengineer next generation peptibodies that have increased IKACh potency and specificity. Successful accomplishment of our proposal should be a major step forward in the deliberate, innovative, and rational development of much needed and effective antifibrillatory agents based on bioengineering approaches that target ion channels important in the mechanism of a major cardiac disease.

Earlier awards

• Cardiac Toxicity of Flavorings in Electronic Nicotine Delivery SystemsFY 2023 · $449K