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Pursuing a PhD: My Journey of Discovery and Future Research Directions Krekwit Shinlapawittayatorn, MD, PhD Cardiac Electrophysiology Research & Training.

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Presentation on theme: "Pursuing a PhD: My Journey of Discovery and Future Research Directions Krekwit Shinlapawittayatorn, MD, PhD Cardiac Electrophysiology Research & Training."— Presentation transcript:

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 21 st, 2011

2 Introduction: Education 2004Doctor of Medicine (M.D.) Chiang Mai University Chiang Mai, Thailand Ph.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 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 Cardiac Sodium Channelopathies: One Gene, Many Diseases SCN5A (Gene) Nav1.5 (Protein) Sudden Infant Death Syndrome Still Birth Brugada Syndrome Cardiac Conduction Defect Sick Sinus Syndrome Dilated Cardiomyopathy Atrial Fibrillation Gain-of- function Loss-of- function Long QT 3 Syndrome

7 Same Genetic Mutation, Different Genetic Disease Phenotype??? 123 Variable Expressivity Incomplete Penetrance

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 Shinlapawittayatorn et al., Heart Rhythm 2011;8(3): H558R H558R+P2006AH558RH558R+P2006A I II H558R H558R+P2006H558RH558R+P2006A I II P2006A H558R

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 1.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): (IF = 4.043) 2.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): (IF = 4.246)

12 4 Other Peer Reviewed Articles 1.Shinlapawittayatorn K, Deschênes I. Sodium Channel Polymorphisms and Arrhythmogenic Events: Pro-Arrhythmic or Anti-Arrhythmic? (in preparation) 2.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) 3.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) 4.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): (IF = 4.218)

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

14 10 Peer Reviewed Abstracts 1.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 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 Kuri B, Nassal DM, Shinlapawittayatorn K, Ficker E, Deschênes I. Identification of KChIP2 in Guinea Pig Heart. Biophys J 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): 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 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 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 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 Shinlapawittayatorn K, Du X, Liu H, Kaufman ES, Deschênes I. A Common SCN5A Polymorphism Restores the Biophysical Defects of LQT3 Mutations. Biophys J 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 Student Best Academic Record, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA

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

17 Acknowledgements MetroHealth Medical Center Case Western Reserve University Ph.D. Thesis Guidance Committee Thomas 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 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 Cardiac Voltage-Gated Sodium Channel (Gene: SCN5A, Protein: Nav1.5) α (260 kD) NH 2 COOH NH 2 2 DIDIIDIIIDIV β2β2β1β1 β (36 kD) S1S2S3S4S5S6S1S2S3S4S5S6S1S2S3S4S5S6S1S2S3S4S5S6 S4 segments:Voltage sensors S5-S6 loops: Pore of the channel Domains III-IV linker: Inactivation gate

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

21 Using Fluorescence Resonance Energy Transfer (FRET) to Examine Sodium Channel Folding CFP Donor YFP Acceptor Excitation FRET Emission FRETc = (I DA – aI AA – dI DD )/I DD C N C N FRET

22 Persistent sodium current Model of Rescued a Gain-of-Function Mutation by the H558R Polymorphism Ventricular myocytes action potential 0 nA Membrane potential (mV) Peak sodium current Na + Defective Inactivation Na + Stabilized Inactivation Inward Outward I Na I Ca IKIK

23 Fragment Design COOH NH N548 L567 R558R558-20aa G538 S577 R558R558-40aa DI DII DIII DIV Nav1.5 N548 L567 H558H558-20aa


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