GENERATION OF A MOUSE MODEL OF EPISODIC ATAXIA TYPE 2 (EA2)
J Ellen
Emory Universitycity: Atlanta country: United States (us)
Grant 7R21NS058596-03 from National Institute Of Neurological Disorders And Stroke
Abstract: Episodic neurological disorders are characterized by attacks of debilitating symptoms interspersed with periods of relatively normal function. Although the symptoms can be diverse, including migraine headache, epilepsy, paralysis, ataxia, and dyskinesia, there are marked similarities in both the genetic etiology and the factors capable of triggering attacks in episodic disorders. Many episodic disorders are associated with ion channel mutations. Further, regardless of the class of ion channelopathy or the expressed symptoms, the precipitants of attacks are most commonly psychological, physical or chemical stressors, suggesting the existence of a common mechanism for the initiation of the attacks. There is little understanding of the mechanisms by which these triggers precipitate neurological dysfunction in individuals who are otherwise normal between attacks. Our approach to this problem is to use a rare monogenic disorder as a model system. because understanding pathogenesis in a monogenic episodic disorder will likely provide insight into genetically complex episodic disorders such as migraine headache and idiopathic epilepsy. We have identified episodic ataxia type 2 (EA2), as a leading candidate for modeling this class of disorders in mice. EA2 is caused by mutations in the CACNA1A gene, which encodes the pore-forming a12.1 subunit of Cav2.1 (P/Q-type) voltage-gated calcium channels. This disorder is particularly amenable for modeling because there is already a wealth of basic information on which to build, including an enormous body of work describing normal and mutant Cav2.1 channel properties in vitro. Individuals with episodic ataxia type 2 experience paroxysmal attacks of migraine, ataxia, and other neurological signs that are triggered by emotional stress, exercise, caffeine or ethanol. Although the mutations in CACNA1A were first identified in 1996, the pathogenic mechanisms are still unknown. Functional expression studies of EA2 mutations in heterologous systems demonstrate reduced Cav2.1 currents, as expected. However, there is evidence for both haploinsufficiency and dominant negative effects of the mutant channel, demonstrating that even this most basic of questions requires expression of the mutants in a native in vivo system. Work in both cultured neurons and mouse mutants also demonstrates that an appreciation of the biophysical properties of the mutant channel in vitro is not likely to provide a comprehensive understanding of the phenotype because compensatory processes in neurons in vivo may also contribute. These results demonstrate the need for a behaviorally intact animal model to fully appreciate disease processes. Therefore, we will develop and characterize a knockin mouse bearing an EA2 mutation. The specific aims of this proposal are 1) To develop and characterize a knockin mouse model of EA2. 2) To behaviorally characterize the EA2 knockin mice. The development of a mouse model will place us in an excellent position to examine pathophysiology and provide insight into human disease. Episodic neurological disorders are characterized by attacks of debilitating symptoms, including migraine headache, epilepsy, paralysis, ataxia, and dyskinesia, interspersed with periods of relatively normal function. There is little understanding of the pathophysiological mechanisms that triggers neurological dysfunction. Therefore, we will develop and characterize a knockin mouse bearing a human mutation for episodic ataxia, a rare monogenic disorder that may provide insight into genetically complex episodic disorders such as migraine headache and idiopathic epilepsy
Keywords: 1, 3, 7-Trimethylxanthine; 1H-Purine-2, 6-dione, 3, 7-dihydro-1, 3, 7-trimethyl-; Abnormal Movements; Absolute ethanol; Address; Alcohol, Ethyl; Animal Model; Animal Models and Related Studies; Antimorphic mutation; Ataxia; Ataxy; base; Behavior; behavior test; Behavioral; behavioral test; Biological Models; Ca(v)2.1; Caffeine; Calcium Channel; Calcium Channel Antagonist Receptor; Causality; Cav2.1; Chemicals; Chromosome Mapping; Class; Complex; Coordination Impairment; Development; Disease; disease causation; disease etiology; disease/disorder; disease/disorder etiology; Disorder; disorder etiology; Dominant Negative; Dominant-Negative Mutant; Dominant-Negative Mutation; Drug Therapy; Dysfunction; Dyskinesias; Dyskinetic syndrome; Dyssynergia; Emotional Stress; epilepsia; Epilepsy; Epileptic Seizures; Epileptics; epileptiform; epileptogenic; Ethanol; Etiology; ETOH; Exercise; Exercise, Physical; experience; experiment; experimental research; experimental study; Functional disorder; Gene Localization; Gene Mapping; Gene Mapping, Total Human and Non-Human; Generations; Genes; Genetic Alteration; Genetic Change; Genetic defect; genetic etiology; genetic mapping; genetic mechanism of disease; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; genetic vulnerability; Genetics, Gene Mapping; genome mutation; Grain Alcohol; Headache, Migraine; human disease; In Vitro; in vivo; Individual; Inherited Predisposition; Inherited Susceptibility; insight; Ion Channel; Ion Channels, Calcium; Ionic Channels; Ions; Linkage Mapping; Mammals, Mice; Membrane Channels; Methylcarbinol; Mice; Mice, Mutant Strains; Migraine; model organism; Model System; Modeling; Models, Biologic; mouse model; mouse mutant; Murine; Mus; mutant; Mutant Strains Mice; Mutation; Nerve Cells; Nerve Unit; Nervous System Diseases; nervous system disorder; Neural Cell; neurobiological; Neurobiology; Neurocyte; Neurologic; Neurologic Disorders; Neurologic Dysfunctions; Neurological; neurological disease; Neurological Disorders; neurological dysfunction; neuronal; Neurons; omega-agatoxin-IVA-sensitive VDCC; Outcome; P-Q type VDCC; Palsy; Paralysed; paralysis; paralytic; Pathogenesis; pathophysiology; Pharmacotherapy; Phenotype; Physiologic; Physiological; Physiology; Physiopathology; Plegia; Position; Positioning Attribute; Process; Property; Property, LOINC Axis 2; psychologic; psychological; Receptors, Calcium Channel Blocker; research study; response; Risk; Seizure Disorder; stressor; Symptoms; System; System, LOINC Axis 4; Testing; tool; V (voltage); VDCC; voltage; voltage-dependent calcium channel (P-Q type); Voltage-Dependent Calcium Channels; Work
Project start date: 2007-05-04
Project end date: 2011-04-30
Budget start date: 1-SEP-2008
Budget end date: 30-APR-2011
PFA/PA: PA-06-181
7R21NS058596-03 (2008): $159201
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to J Ellen
AN INTERVENTION FOR PROMOTING SMOKE-FREE POLICY IN RURAL KENTUCKY
J Ellen, Professor
University Of Kentuckycity: Lexington country: United States (us)
Grant 5R01HL086450-05 from National Heart, Lung, And Blood Institute
Abstract: The purpose of this study is to test the effects of a community intervention on smoke-free policy outcomes in rural underserved communities. The intervention combines assessment of community readiness with tailored, evidence-based dissemination and implementation strategies. Rural residents are more likely to be exposed to secondhand smoke than those living in urban areas, reflecting a major rural-urban disparity in smoke-free laws. The overall goal of the study is to accelerate the ´diffusion-of-innovations curve´ in rural communities through tailored, evidence-based dissemination and implementation efforts. The long-term goal is to develop a best practices framework for disseminating scientific knowledge about the effects of secondhand smoke and smoke-free laws and implementing effective community policy change and maintenance strategies in rural underserved communities. A pretest posttest, three-group quasi- experimental design will be used to test the primary hypotheses Controlling for contextual factors, (a) the overall change in stage of readiness for smoke-free policy will be greater for Treatment than Control communities; (b) media coverage will be more favorable toward smoke-free environments in Treatment than Control communities; and (c) Treatment communities will be more likely than Control communities to demonstrate smoke-free policy outcomes. Guided by a community readiness model, the Intervention will have two components (1) assessment of community stage of readiness; and (2) stage-specific, tailored dissemination and implementation strategies. The main elements of Component II of the Intervention include translating and disseminating knowledge, and building capacity and demand for smoke-free policy. The Treatment communities (n = 20) will participate in both components of the Intervention. Control I communities (n = 10) will participate in the community assessment of readiness at baseline and annually. The Control II communities (n = 10) will participate in community assessment of stage of readiness at the end of the study only. Community stakeholders will participate in key informant telephone interviews to assess community readiness for smoke-free policy. Print media clippings from all 51 daily and non-daily newspapers in study counties will be evaluated for pro/con slant related to smoke-free environments. Initial, intermediate, and final smoke-free policy outcomes will be measured. The potential influence of secular trends on the impact of this community intervention will be analyzed. The proposal is directly relevant to public health in that it has the potential to protect residents in rural, underserved communities from premature death and disease from exposure to secondhand smoke
Keywords: Affect; Air; Cessation of life; Clip; Communities; community intervention; contextual factors; Controlled Study; County; Diffusion of Innovation; Disease; dissemination research; Elements; Environment; evidence base; Experimental Designs; Exposure to; Goals; Health; implementation research; informant; innovation; Intervention; Kentucky; Knowledge; Laws; Life; Maintenance; Measures; Modeling; Newspapers; NIH Program Announcements; Outcome; outreach; Policies; Population; population based; premature; Printed Media; public education; public health medicine (field); Public Health Practice; public policy on tobacco; Readiness; Research; Resources; Rural; Rural Community; Science; Smoke; Staging; Telephone Interviews; Testing; Time; tobacco control; tobacco exposure; Tobacco use; Translating; trend; urban area
Project start date: 2007-04-01
Project end date: 2012-02-28
Budget start date: 1-MAR-2011
Budget end date: 28-FEB-2012
PFA/PA: PAR-06-039
5R01HL086450-05 (2011): $579266
5R01HL086450-04 (2010): $622856
SYSTEMS ENGINEERING FOCUS ON CLINICAL INFORMATICS
J Ellen, Assistant Professor
University Of Virginia Charlottesvillecity: Charlottesville country: United States (us)
Grant 5T15LM009462-05 from National Library Of Medicine
Abstract: The goal of this training program is to bring systems engineering students and faculty into the healthcare field through the discipline of clinical informatics, which we believe is a natural fit, and to break down the barriers between systems engineering and healthcare research through close collaboration over common research goals. The National Academy of Engineering (NAE) and Institute of Medicine (IOM) 2005 report entitled "Building a Better Delivery System A New Engineering/Health Care Partnership" identified system failures in current healthcare delivery and recommended an interdisciplinary approach to solving these problems based on information technology and systems engineering (SE). It identified key barriers to this strategy, including differences between the healthcare and engineering disciplines in "methods, metrics, values and mind-sets." We propose a new strategy for research training in clinical informatics responding directly to the problems identified in the report. This strategy builds on existing successful collaborations between the Department of Systems and Information Engineering in the School of Engineering and Applied Science at the University of Virginia (UVa) and several units in UVa´s School of Medicine, including the Division of Clinical Informatics in the Department of Public Health Sciences. Our program creates PhD and postdoctoral training opportunities designed to attract students and established researchers from other fields to address challenging clinical informatics questions. The program inherits a framework from the existing substantial SE graduate program, with unique curricular and research components. The core curriculum includes formal introductions to clinical informatics, SE, and the structure and operation of healthcare delivery systems. Subsequent alternative tracks for training include human-automation interaction, computational statistics and simulation, risk and decision analysis, systems integration, and optimization and control. Research projects are collaborative, with trainees having both healthcare and engineering mentors as they conduct research using systems engineering and medical informatics approaches applicable to improved healthcare delivery and training. We anticipate that this collaborative approach to training will lead to fundamental advances in clinical informatics with a trained set of researchers who will continue to develop the field, thereby addressing the needs articulated by the NAE and IOM
Keywords: Academy; Address; Applied Research; Automation; base; Clinical Informatics; Collaborations; Decision Analysis; design; Discipline; Doctor of Philosophy; Educational Curriculum; Engineering; Faculty; Failure (biologic function); Goals; health care delivery; Health Sciences; Health Services Research; Healthcare; Human; improved; Information Systems; Inherited; Institute of Medicine (U.S.); interdisciplinary approach; Lead; Medical Informatics; medical schools; Mentors; Methods; Metric; Mind; operation; post-doctoral training; Problem Solving; programs; public health medicine (field); Reporting; Research; Research Personnel; Research Project Grants; Research Training; Risk; Schools; simulation; statistics; Structure; Students; System; Systems Integration; Training; Training Programs; Universities; Virginia
Project start date: 2007-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-LM-06-001
5T15LM009462-05 (2011): $423650
GENERATION OF A MOUSE MODEL OF L-DOPA-RESPONSIVE DYSTONIA (DRD)
J Ellen
Emory Universitycity: Atlanta country: United States (us)
Grant 7R21NS059645-03 from National Institute Of Neurological Disorders And Stroke
Abstract: Dystonia is the third most common movement disorder, after essential tremor and Parkinson disease, with a prevalence of ~330 per million. Dystonia is broadly characterized by simultaneous and sometimes sustained contractions of agonist and antagonist muscles. These co-contractions result in twisting movements and postures that have a wide range of speed, amplitude and rhythmicity that varies among patients. The general goal of our research is to understand the pathophysiology of dystonia. Unlike Parkinson disease or Huntington disease where neurodegeneration provides clues to the pathogenesis of the movement disorder, idiopathic dystonia is a functional movement disorder without obvious markers or cell death to help define pathophysiology. Despite a strong clinico-pathological correlation between the basal ganglia and dystonia, there is little understanding of the underlying neuronal dysfunction. Moreover, the few animal models of dystonia associated with basal ganglia function are of limited value because the pathophysiology is inconsistent with abnormalities in human dystonias. Our approach to this problem is to model a monogenic dystonic disorder to provide broad insight into pathophysiological mechanisms. We have identified L-DOPA responsive dystonia (DRD), as a leading candidate for modeling dystonia associated with basal ganglia dysfunction. DRD is caused by mutations in genes encoding either GTP cyclohydrolase or tyrosine hydroxylase (TH) and is characterized by early onset generalized dystonia that is ameliorated after administration of low doses of L-DOPA, the metabolic precursor of dopamine. DRD caused by mutations in TH is particularly amenable for modeling because there is already a wealth of basic information on which to build, including an enormous body of work describing normal TH function and dopaminergic regulation of motor control. Therefore, we will develop and characterize a knockin mouse bearing a human mutation in TH that is associated with DRD. Therefore, we will develop and characterize a knockin mouse bearing an EA2 mutation. The specific aims of this proposal are 1) to develop and characterize a knockin mouse model of DRD. 2) To behaviorally characterize the DRD knockin mice. Development and characterization of an animal model exhibiting basal ganglia dysfunction that is mechanistically faithful and reliably reproducible is critical to understanding pathophysiology in dystonia and essential for developing novel therapeutics. Dystonia is the third most common movement disorder with a prevalence of ~330 per million. Dystonia is broadly characterized by simultaneous and sometimes sustained contractions of agonist and antagonist muscles. There is little understanding of the pathophysiological mechanisms underlying dystonia. Therefore, we will develop and characterize a knockin mouse bearing a human mutation that causes L-DOPA-responsive dystonia to provide insight into general pathomechanisms underlying dystonia
Keywords: 3, 4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1, 2-benzenediol; 7, 8-Dihydroneopterintriphosphate Synthetase; Agonist; Animal Model; Animal Models and Related Studies; Basal Ganglia; Basal Nuclei; base; behavior test; Behavioral; behavioral test; Benign Essential Tremor; body movement; Cell Death; Clinical; Cyclicity; design; designing; Development; Dopamine; Dose; Dysfunction; Dyskinesia Syndromes; Dystonia; Dystonia Disorders; Dystonic Disorder; early onset; Essential Tremor; Exhibits; expectation; Functional disorder; Generations; Genes; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Goals; GTP 7, 8-8, 9-dihydrolase; GTP 8-Formylhydrolase; GTP Cyclohydrolase; GTP Dihydrolase; GTP Ring-Opening Enzyme; Human; human disease; Human, General; Huntington Chorea; Huntington Disease; Huntington`s; Huntington`s Disease; Huntington`s Disease Pathway; Huntingtons Disease; Hydroxytyramine; Idiopathic Parkinson Disease; insight; L-Tyrosine, tetrahydrobiopterin[{..}]oxygen oxidoreductase (3-hydroxylating); Lewy Body Parkinson Disease; Mammals, Mice; Man (Taxonomy); Man, Modern; Metabolic; Mice; model organism; Modeling; Molecular; Motor; motor control; mouse model; Movement; Movement Disorder Syndromes; Movement Disorders; Murine; Mus; Muscle; Muscle Cell Contraction; Muscle Contraction; Muscle Dystonia; Muscle Tissue; Muscular Contraction; Mutation; Nature; necrocytosis; Nerve Degeneration; Nervous System Diseases; nervous system disorder; neural degeneration; neurodegeneration; Neurologic Disorders; neurological disease; Neurological Disorders; Neuron Degeneration; neuronal degeneration; Neuronal Dysfunction; new therapeutics; next generation therapeutics; novel therapeutics; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pathogenesis; pathophysiology; Patients; Periodicity; Phenotype; Physiopathology; Posture; Prevalence; Primary Parkinsonism; Progressive Chorea, Hereditary, Chronic (Huntington); Range; Regulation; Research; Rhythmicity; Risk; Speed; Speed (motion); tool; Tyrosine 3-Monooxygenase; Tyrosine Hydroxylase; Work
Project start date: 2007-07-01
Project end date: 2011-06-30
Budget start date: 1-SEP-2008
Budget end date: 30-JUN-2011
PFA/PA: PA-06-181
7R21NS059645-03 (2008): $195334