THE ROLE OF RGS PROTEINS IN THE PARASYMPATHETIC CONTROL OF HEART RATE
A Kirill
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 5R01HL105550-02 from National Heart, Lung, And Blood Institute
Keywords: Ablation; Address; Animal Model; Animals; Arrhythmia; base; Biochemical; Biological; Bradycardia; Cardiac; Cardiac Output; Complement; Complex; Data; Dependence; design; Development; Electrocardiogram; Electrophysiology (science); Equilibrium; Family; G-Protein Signaling Pathway; Genetic; genetic manipulation; Goals; GTP-Binding Protein beta Subunits; GTP-Binding Protein Regulators; GTP-Binding Proteins; Heart; Heart Atrium; heart function; Heart Rate; insight; interest; Laboratories; Mediating; member; Molecular; mouse model; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Muscle Cells; Nervous system structure; novel; novel therapeutic intervention; Outcome Measure; Outcome Study; Pharmacology; Physiological; Physiology; Potassium Channel; prevent; Process; Protein Family; public health relevance; Reagent; receptor; reconstitution; Regulation; Research; Research Infrastructure; Research Proposals; RGS Proteins; Role; Signal Pathway; Signal Transduction; Specificity; Structure; System; Telemetry; Testing; Therapeutic Intervention; therapy design; Work
Relevance: Normal heart function depends on a healthy balance between excitatory and inhibitory signals provided by the nervous system. Imbalance in this critical cardiac regulatory system can trigger arrhythmias, often with fatal consequences. The work proposed herein will yield a clearer understanding of the molecules involved in the regulation of cardiac output by the nervous system and thus will aid in the rational design of effective therapeutic interventions aimed at treating or preventing arrhythmias
Project start date: 2011-01-15
Project end date: 2014-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01HL105550-02 (2012): $339750
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Kirill
MOLECULAR BASIS OF RGS PROTEIN FUNCTION IN THE STRIATUM
A Kirill
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 5K02DA026405-03 from National Institute On Drug Abuse
Abstract: This is an application for the NIDA sponsored K02 Independent Scientist Award. The long term goal of the candidate is to elucidate the mechanisms of G protein signaling regulation in the basal ganglia as a necessary prerequisite to understanding neurological diseases and addiction and developing means of their treatment. The main focus of the research proposal is on the central regulator of opioid and dopamine G protein signaling, RGS9-2 that has been implicated in addiction and drug abuse. We have recently discovered that RGS9-2 in the striatum exists in a complex with a novel neuronal protein which we named R7 Binding Protein (R7BP). The HYPOTHESIS addressed by this proposal is that R7BP serves as a critical regulator of RGS9-2 function in the striatal neurons by controlling the expression level, localization, and activity of RGS9-2. This hypothesis will be addressed in the following SPECIFIC AIMS 1. to determine the mechanisms by which R7BP controls expression of RGS9-2 in striatal neurons. 2. To understand the role of R7BP in the regulation of RGS9-2 catalytic activity. 3. To further characterize the molecular composition of G protein inactivating complex in striatal neurons. In addition to pursuing the research goals, plans to undertake career development activities by (I) establishing and/or maintaining active collaborations with leading researchers focusing on drug addiction mechanisms, (II) integrating my research program into the larger community efforts to understand mechanisms of drug addiction and (III) learning cutting edge behavioral and imaging approaches to study drug addiction and implanting them to pursue the research directions in the laboratory. The studies should provide an insight into the mechanisms that regulate reward processing in the basal ganglia of the brain. This knowledge will be important for better understanding of how drugs of abuse lead to addiction with the hopes for the future development of therapeutical intervention strategies
Keywords: addiction; Address; Affect; Basal Ganglia; base; Behavior Control; Behavioral; Binding (Molecular Function); Binding Proteins; Biochemical; Biological; Biological Assay; Brain; career development; Cell membrane; Collaborations; Communities; Complex; Corpus striatum structure; Data; density; design; Development; Dopamine; Drug abuse; Drug Addiction; Drug Implants; drug of abuse; Drug Tolerance; Employee Strikes; Family member; Future; G-Protein Signaling Pathway; Gene Delivery; Goals; GTP Binding; GTP-Binding Protein Regulators; GTP-Binding Proteins; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; Hydrolysis; Image; improved; In Vitro; Independent Scientist Award; insight; Intervention; Kinetics; Knowledge; Laboratories; Lead; Learning; Locomotion; Mediating; Membrane; Mental disorders; Molecular; Names; National Institute of Drug Abuse; nervous system disorder; Neurons; novel; Opioid; Pain; Pathway interactions; Perception; Play; postsynaptic; Process; programs; protein complex; protein expression; Protein Family; protein function; protein protein interaction; Proteins; Proteolysis; Proteomics; Reaction; Regulation; Research; Research Personnel; Research Proposals; response; reward processing; RGS Proteins; RNA Interference; Role; Signal Pathway; Signal Transduction; Site; Specificity; Speed (motion); Testing; Therapeutic; Validation; Viral
Project start date: 2009-04-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-06-527
5K02DA026405-03 (2011): $119943
7K02DA026405-04 (2011): $108272
5R01DA021743-06 (2011): $326088
7R01DA021743-05 (2010): $143439
REGULATION OF SIGNALING IN THE RETINA BY RGS PROTEINS
A Kirill
Scripps Floridacity: Jupiter country: United States (us)
Grant 7R01EY018139-05 from National Eye Institute
Abstract: G protein signaling pathways in the retina are critically involved in reception and transduction of visual stimuli. The physiological operation of these pathways is dependent on the tight control of signal duration mediated by the Regulators of G protein signaling (RGS) proteins. Our long term goal is to elucidate the functional role of RGS protein in the retina signaling as a necessary prerequisite to understanding visual dysfunctions and therapeutic means of their treatment. The main focus of this proposal is on the R7 family of RGS proteins that are expressed in the retina where they control the rate of G protein inactivation during visual signal transmission. Research over the past several years have established the functional role of one R7 RGS member, RGS9, which utilizes a complex network of macromolecular interactions to shape the response of photoreceptors to light. The central HYPOTHESIS of this study is that the functional principles of RGS9 in photoreceptors also govern the function of other homologous R7 RGS proteins in retina neurons. We, therefore, suggest to utilize the wealth of methodological approaches and concepts developed in the studies of RGS9 in photoreceptors to gain insights into the organization and functional regulation of R7 RGS proteins through their macromolecular interactions. Specifically, our hypothesis will be addressed in the following SPECIFIC AIMS 1. To elucidate the molecular mechanism of Gbeta5 action. We will perform detailed molecular and kinetic analysis to analyze how Gbeta5 regulates the activity of R7 RGS proteins. 2. To determine the functional significance of R7 RGS association with their membrane anchor, R7BP (R7 Binding Protein) using mouse models. Using mouse transgenic and knockout technology we will address the role of this newly discovered regulator of R7 RGS proteins in the retina. 3. To identify G proteins regulated by R7 RGS proteins in retina neurons. These studies should provide a better understanding of the regulation of signaling in the retina and generate insights into the molecular mechanisms of G protein signal disruption that lead to visual disorders and blindness
Keywords: Address; base; Binding (Molecular Function); Binding Proteins; Biological Assay; Blindness; Complex; Cues; density; Disease; Family; Functional disorder; G-Protein Signaling Pathway; gain of function; genetic manipulation; Goals; GTP-Binding Protein beta Subunits; GTP-Binding Protein Regulators; GTP-Binding Proteins; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Homologous Gene; Human; Hydrolysis; Impairment; Individual; insight; Kinetics; Knock-out; Knockout Mice; Lead; Light; Literature; loss of function; Mass Spectrum Analysis; Mediating; member; Membrane; Molecular; mouse model; Mus; Neurons; novel; operation; Pathway interactions; Patients; Photoreceptors; Physiological; programs; protein complex; protein expression; protein protein interaction; Proteins; Regulation; Research; Research Personnel; research study; Resolution; response; Retina; RGS Domain; RGS Proteins; Role; Shapes; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Specific qualifier value; Stimulus; Structure; Surface; Synapses; Technology; Testing; Therapeutic; Transducin; Transgenic Mice; Transgenic Organisms; transmission process; Vision Disorders; Visual; Visual Signal Transduction Pathway; visual stimulus
Project start date: 2007-04-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
7R01EY018139-05 (2011): $422111
THE ROLE OF RGS PROTEINS IN THE PARASYMPATHETIC CONTROL OF HEART RATE
A Kirill, Associate Professor
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 1R01HL105550-01 from National Heart, Lung, And Blood Institute
Abstract: Cardiac output adjusts on a beat-to-beat basis due to the changing balance of parasympathetic and sympathetic input to the heart. G protein signaling pathways are fundamental to this important process. Indeed, the prototypical signaling pathway consisting of the type 2 muscarinic acetylcholine receptor (m2R) and the G protein-gated atrial potassium channel IKACh mediates in large part the inhibitory effects of parasympathetic activity on the heart. Too much or too little parasympathetic influence on the heart can trigger arrhythmias, often with fatal consequences. The long-term goal of our research is to identify and characterize molecular mechanisms that control or impact m2R-IKACh signaling, and consequently, the parasympathetic regulation of the heart. This application capitalizes on the recent discovery that IKACh associates physically with a regulatory complex consisting of the sixth member of the Regulator of G protein Signaling protein family (Rgs6) and the fifth member of the G protein beta subunit family (G¿5). The interaction between Rgs6/ G¿5 and IKACh has clear functional implications, as temporal aspects of m2R-IKACh signaling are altered in atrial myocytes from mice lacking Rgs6. Together, these preliminary data suggest the central hypothesis of this proposal, namely that Rgs6/ G¿5 serves as a negative regulator of m2R-IKACh signaling in the heart, with a corresponding and predictable influence on the parasympathetic control of cardiac output. This hypothesis will be tested by pursuing three complementary Specific Aims (1) To understand the molecular organization and functional significance of the Rgs6/ G¿5 -IKACh complex, (2) To define the impact of Rgs6/ G¿5 on m2R-IKACh signaling in atrial myocytes, and (3) To understand the significance of the Rgs6/ G¿5 complex to cardiac physiology. The strategy proposed to address these aims will entail a synergistic combination of biochemical, molecular biological, electrophysiological, and physiological approaches, each exploiting the existence of a powerful array of reagents and animal models. Successful completion of these studies will yield detailed insights into the molecular determinants of Rgs6/ G¿5 -IKACh complex assembly and a clear understanding of the functional correlates of complex formation on m2R-IKACh signaling as assessed in the well-controlled expression system, the native context of the atrial myocyte, and the whole animal. By leveraging the unique strengths and research infrastructures of two laboratories, this project is poised to reveal novel insights into the organization and regulation of G protein signaling pathways and the parasympathetic regulation of cardiac output. As such, this information could prove useful for the development of novel therapeutic interventions designed to prevent or treat certain types of arrhythmia. Normal heart function depends on a healthy balance between excitatory and inhibitory signals provided by the nervous system. Imbalance in this critical cardiac regulatory system can trigger arrhythmias, often with fatal consequences. The work proposed herein will yield a clearer understanding of the molecules involved in the regulation of cardiac output by the nervous system and thus will aid in the rational design of effective therapeutic interventions aimed at treating or preventing arrhythmias
Keywords: Ablation; Address; Agents, Muscarinic; Animal Model; Animal Models and Related Studies; Animals; Arrhythmia; Atrial; atrium; Auricle of Heart; balance; balance function; base; Biochemical; Biological; biological signal transduction; Bradycardia; Cardiac; Cardiac Arrhythmia; Cardiac Atrium; Cardiac Output; Cell Communication and Signaling; Cell Signaling; Chronotropism, Cardiac; Chronotropisms, Cardiac; Complement; Complement Proteins; Complex; Data; Dependence; design; designing; Development; ECG; EKG; Electrocardiogram; Electrocardiography; Electrophysiology; Electrophysiology (science); Equilibrium; Family; G-Protein beta Subunit; G-Protein Regulating Factors; G-Protein Signaling Pathway; G-Proteins; Genetic; genetic manipulation; Goals; GTP-Binding Protein beta Subunits; GTP-Binding Protein Regulators; GTP-Binding Proteins; GTP-Regulatory Proteins; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; Heart; Heart Arrhythmias; Heart Atrium; heart function; heart output; Heart Rate; Infrastructure; insight; interest; intervention design; intervention therapy; Intracellular Communication and Signaling; Ion Channels, Potassium; K channel; Laboratories; Mammals, Mice; Mediating; member; Mice; model organism; Molecular; mouse model; Murine; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Muscle Cells; Muscle Cells, Mature; Myocytes; Nervous System; Nervous system structure; Neurologic Body System; Neurologic Organ System; Neurophysiology / Electrophysiology; novel; novel therapeutic intervention; NRVS-SYS; Outcome Measure; Outcome Study; Pharmacology; Physiologic; Physiological; Physiology; Potassium Channel; prevent; preventing; Process; Protein Family; public health relevance; Reagent; receptor; Receptor Protein; Receptors, Muscarinic; reconstitute; reconstitution; Regulating Factors, GTP-Binding Protein; Regulation; Regulators of G-Protein Signaling Proteins; Regulators, G-Protein Signaling; Research; Research Infrastructure; Research Proposals; RGS Family Protein; RGS Protein (G-Protein Signaling); RGS Proteins; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Pathway from G-Protein Families; social role; Specificity; Structure; System; System, LOINC Axis 4; Telemetries; Telemetry; Testing; Therapeutic Intervention; therapy design; treatment design; Work
Relevance: Normal heart function depends on a healthy balance between excitatory and inhibitory signals provided by the nervous system. Imbalance in this critical cardiac regulatory system can trigger arrhythmias, often with fatal consequences. The work proposed herein will yield a clearer understanding of the molecules involved in the regulation of cardiac output by the nervous system and thus will aid in the rational design of effective therapeutic interventions aimed at treating or preventing arrhythmias
Project start date: 2011-01-15
Project end date: 2014-11-30
Budget start date: 15-JAN-2011
Budget end date: 30-NOV-2011
PFA/PA: PA-10-067
1R01HL105550-01 (2011): $377500