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Pursuing a PhD: My Journey of Discovery and Future Research Directions

Pursuing a PhD: My Journey of Discovery and Future Research Directions. Krekwit Shinlapawittayatorn, MD, PhD Cardiac Electrophysiology Research & Training Center (CERT) Department of Physiology, Chiang Mai University November 21 st , 2011. Introduction: Education.

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Pursuing a PhD: My Journey of Discovery and Future Research Directions

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  1. Pursuing a PhD: My Journey of Discovery and Future Research Directions Krekwit Shinlapawittayatorn, MD, PhD Cardiac Electrophysiology Research & Training Center (CERT) Department of Physiology, Chiang Mai University November 21st, 2011

  2. Introduction: Education 2004Doctor of Medicine (M.D.) Chiang Mai University Chiang Mai, Thailand 2006-2011Ph.D. (Physiology & Biophysics) Case Western Reserve University Cleveland, OH, USA

  3. Case Western Reserve University (CWRU) and Department of Physiology and Biophysics CWRU was founded in 1826. CWRU is a private research university located in Cleveland, OH, USA. The University is associated with 16 Nobel Laureates. The department is currently ranked #9 based on NIH funding.

  4. Dissertation Modulations of Sodium Channel Long QT and Brugada Syndrome Mutations by a Common Sodium Channel Polymorphism

  5. Genetic Defects of Cardiac Ion Channels: From the Bench to Bedside

  6. SCN5A (Gene) Nav1.5 (Protein) Gain-of-function Loss-of-function Cardiac Sodium Channelopathies: One Gene, Many Diseases Brugada Syndrome Sick Sinus Syndrome Cardiac Conduction Defect Atrial Fibrillation Still Birth Dilated Cardiomyopathy Sudden Infant Death Syndrome Long QT 3 Syndrome

  7. Same Genetic Mutation, Different Genetic Disease Phenotype??? 1 2 3 Incomplete Penetrance Variable Expressivity

  8. Why do phenotypes show differences in penetrance and expressivity??? Unresolved Question:

  9. Pedigree of an Asymptomatic Family Carrying a Gain-of-Function Mutation of Sodium Channels I I 1 1 2 2 H558R H558R H558R H558R H558R+P2006A H558R+P2006A II II 1 1 2 2 H558R H558R H558R+P2006 H558R+P2006A H558R H558R H558R+P2006A H558R+P2006A H558R P2006A Shinlapawittayatorn et al., Heart Rhythm 2011;8(3):455-62

  10. General hypothesis This led us to hypothesize that sodium channel H558R polymorphism may contribute to the genotype-phenotype discordance observed in heritable arrhythmias by acting as diseases modifying gene.

  11. 2 Peer Reviewed Articles From PhD Project Shinlapawittayatorn K, Dudash L, Poelzing S, Ficker E, and Deschênes I. Cardiac Sodium Channel Fragments Spanning H558R Polymorphism Rescue Defective Trafficking of a Brugada Syndrome Mutation. Circ Cardiovasc Genet 2011;4(5):500-9. (IF = 4.043) Shinlapawittayatorn K,Du X, Liu H, Ficker E, Kaufman ES, Deschênes I. A Common SCN5A Polymorphism Restores the Biophysical Defects of SCN5A Mutations. Heart Rhythm 2011;8(3):455-62. (IF = 4.246)

  12. 4 Other Peer Reviewed Articles Shinlapawittayatorn K, Deschênes I. Sodium Channel Polymorphisms and Arrhythmogenic Events: Pro-Arrhythmic or Anti-Arrhythmic? (in preparation) Shinlapawittayatorn K,Sorrentino S, Forleo C, Anaclerio M, Iacoviello M, Guida P, Favale S, Ficker E, Santis DD, Nalin I, Deschênes I. Evidence for a Novel Gene (KCNQ1) Underlying Brugada Syndrome. (in preparation) Abu Jawdeh BG, Khan S, Deschênes I, Hoshi M, Goel M, Lock JT, Shinlapawittayatorn K, Babcock G, Lakhe-Reddy S, DeCaro G, Yadav SP, Mohan ML, Naga Prasad SV, Schilling WP, Ficker E, and Schelling JR. Phosphoinositide Binding Differentially Regulates NHE1 Na+/H+ Exchanger-Dependent Proximal Tubule Cell Survival. J Biol Chem 2011 (in press, IF = 5.328) Hsu K, Han J, Shinlapawittayatorn K, Deschênes I, Marbán E. Membrane Potential Depolarization As a Triggering Mechanism for Vpu-Mediated HIV-1 Release. Biophysical Journal 2010;99(6):1718-25. (IF = 4.218)

  13. 1 Editorial Comments Shinlapawittayatorn K, Deschênes I. Alteration of Tyrosine Kinase Signaling: Another Player in the Arrhythmogenesis of Atrial Fibrillation? Heart Rhythm 2010;7(9):1253-4. (IF = 4.246)

  14. 10 Peer Reviewed Abstracts Shinlapawittayatorn K,Du X, Liu H, Nassal DM, Liu H, Enweane P, Deschênes I. A Novel Loss-of-Function Mechanism for Brugada Syndrome Sodium Channel Mutations. Heart Rhythm 2011. Shinlapawittayatorn K,Nassal DM, Liu H, Ficker E, Deschênes I. Dominant-Negative Suppression of Sodium Channel Activity By a Brugada Syndrome Mutation Observed in Cardiomyocytes. Biophys J 2011. Kuri B, Nassal DM, Shinlapawittayatorn K, Ficker E, Deschênes I. Identification of KChIP2 in Guinea Pig Heart. Biophys J 2011. Du X, Enweana P, Shinlapawittayatorn K, Liu H, Deschênes I. A Novel Mechanism of Action for Sodium Channel Brugada Syndrome Mutations. Heart Rhythm 2010;7(11):1716. Shinlapawittayatorn K,Du X, Liu H, Ficker E, Deschênes I. Do Sodium Channel α-α. Interactions Contribute to Loss-of-Function Observed in Brugada Syndrome? Biophys J 2010. Sorrentino S, Shinlapawittayatorn K, Forleo C, Anaclerio M, Iacoviello M, Nalin I, De Santis D, Zaccaria M, Ficker E, Guida P, Deschênes I, Favale S. Evidence for a Novel Gene (KCNQ1) Underlying Brugada Syndrome. Societa Italiana di Cardiologia-70○ Congresso Nazionale 2009. Sorrentino S, Shinlapawittayatorn K, Forleo C, Anaclerio M, Iacoviello M, De Santis D, Nalin I, Ficker E, Favale S, Deschênes I. A Novel Gene (KCNQ1) Is Involved in Brugada Syndrome. ESC Congress 2009. Shinlapawittayatorn K,Sorrentino S, Anaclerio M, Guida P, Iacoviello M, Favale S, Ficker E, Forleo C, Deschênes I. Evidence for a Novel Gene (KCNQ1) Underlying Brugada Syndrome. Heart Rhythm 2009. Shinlapawittayatorn K,Du X, Liu H, Kaufman ES, Deschênes I. A Common SCN5A Polymorphism Restores the Biophysical Defects of LQT3 Mutations. Biophys J 2009. Shinlapawittayatorn K,Kaufman ES, Deschênes I. SCN5A Polymorphism Decreases Arrhythmogenic Events in a Family Carrying a LQT3 Mutation. Biophys J 2008;94:3087.

  15. Honors and Awards 2011Finalist of Student Research Achievement Award (Category: Membrane Biophysics), 55nd Annual Meeting of the Biophysical Society, Baltimore, Maryland, USA 2009First Place Graduate Student Poster Presentation (Department Annual Retreat), Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA 2009First Place of the Trainee’s Poster Presentation Competition (Research Festival), MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA 2008American Heart Association Pre-doctorol Fellowship Award (Percentile Rank: 0.93), American Heart Association, Great Rivers Affiliate, USA 2008Finalist of Student Research Achievement Award (Category: Membrane Biophysics), 52nd Annual Meeting of the Biophysical Society, Long Beach, California, USA 2007First Place of the Trainee’s Oral Presentation Competition (Genetic Basis of Cardiovascular Disease), MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA 2007Recknagel Graduate StudentBest Academic Record, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA

  16. Patch clamp recording facility (research and training) - Isolated cardiomyocytes - Drug screening - Molecular autopsy - Personalized medicine: patient-specific iPSC TRF research grant for new scholar Future Directions

  17. Acknowledgements Ph.D. Thesis Guidance CommitteeThomas M. Nosek, PhD George R. Dubyak, PhD Stephen W. Jones, PhD Kevin J. Donahue, MD Kenneth R. Laurita, PhD Robert D. Harvey, PhD Isabelle Deschênes, PhD Case Western Reserve University MetroHealth Medical Center Chiang Mai Medical School CERT Center Nipon Chattipakorn, MD, PhD

  18. Thank You For Your Attention “nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual form of nature, by careful investigation of the rarer forms of disease” William Harvey (1657)

  19. DI DII DIII DIV α (260 kD) β (36 kD) + + + + + + + + β2 β1 COOH COOH NH 2 S1 S1 S1 S1 S2 S2 S2 S2 S3 S3 S3 S3 S4 S4 S4 S4 S5 S5 S5 S5 S6 S6 S6 S6 COOH NH NH 2 2 Cardiac Voltage-Gated Sodium Channel (Gene: SCN5A, Protein: Nav1.5) S4 segments:Voltage sensors S5-S6 loops: Pore of the channel Domains III-IV linker: Inactivation gate

  20. Heterologous Expression of Nav1.5 Patch clamp SCN5A-WT SCN5A-P2006A SCN5A-H558R-P2006A Nav1.5 GFP-IRES Vector HEK293 cells Fluorescence HEK HEK HEK cells cells cells 1 day

  21. Using Fluorescence Resonance Energy Transfer (FRET) to Examine Sodium Channel Folding CFP YFP Acceptor Emission FRETc = (IDA – aIAA – dIDD)/IDD FRET Excitation Donor C N N C FRET

  22. Model of Rescued a Gain-of-Function Mutation by the H558R Polymorphism 30 IK Na+ 0 INa ICa Na+ -30 Inward Outward -60 -90 Defective Inactivation Stabilized Inactivation Persistent sodium current Ventricular myocytes action potential 1 2 3 0 Membrane potential (mV) 4 4 0 nA Peak sodium current

  23. Fragment Design 282 558 R558-40aa R558-20aa H558-20aa G538 N548 N548 R558 H558 R558 L567 L567 S577 Nav1.5 DI DII DIII DIV + + + + + + + + NH2 COOH

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