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The Tomaselli lab is focused on the fundamental basis of excitability in the heart. We study this problem at multiple levels of integration from molecules and cells to abnormalities of heart rhythm in patients.
At a molecular level, they seek to understand how ion channel proteins perform their essential tasks, in particular they are interested in a key paradox how these channels permit the flow of millions of ions a second, yet do this with exquisite selectivity (sodium channels allow sodium ions but not similarly sized and charged potassium ions).
More recently they have turned their attention to the regulation of sodium and potassium channels by important cellular signaling systems which are involved in not only in how the heart conducts electricity but also the force with which it contracts.
The diseased heart undergoes a series of changes, initially compensatory but ultimately maladaptive, that increase the risk of potentially lethal arrhythmias. These changes are commonly referred to as remodeling. Dr. Tomaselli’s group is studying the remodeling process in animal models of heart failure using gene expression, protein and ionic current measurements. They have developed a canine microarray for the broad-based study of gene expression in the failing canine heart.
At the ultimate level of integration they are examining the role of implanted defibrillators (ICDs) in patients with diseased, remodeled hearts. They have initiated a study referred to as PROSe-ICD (PRospective Observational Study of the ICD in the prevention of sudden death).
PROSe-ICD has enrolled nearly 800 patients all have undergone detailed clinical and electrocardiographic studies as well as having blood collected for performing genetic and proteomic analyses. Over 25% of this cohort has undergone detailed cardiac imaging (MR and CT) and spectroscopy to identify imaging based markers of risk of sudden death. The overarching goal is to better understand the mechanisms of sudden arrhythmic death and to develop better predictors of risk of this devastating outcome.
Donald W. Reynolds Center in Cardiovascular Clinical Research 2003 – 2010
Robert Weiss, Director, G.Tomaselli Co-Director and PI: PROSE –ICD
RO1 HL091062 (PI: Tomaselli) 2009 – 2014
“Fundamental Biology of Sudden Cardiac Death and Its Application to Identify Patient at Risk”
This grant will examine the role of genetic, protein and electrocardiographic markers measured longitudinally in predicting the risk of SCD and overall mortality in patients with implantable defibrillators placed for primary prevention.
R33 HL087363 (PI: Tomaselli) 2007 – 2010
“The System Biology of Sudden Cardiac Death”, Cluster Project 2
Cluster Project 2 will extend prior HF work to the tissue level by testing the hypothesis that regional (transmural) changes in the expression of SL ion channels, proteins involved in intracellular Ca2+-cycling and connex in proteins lead to regional heterogeneity of AP repolarization and thus increased risk for arrhythmia in the setting HF.
RO1 HL50411-14 (PI: Tomaselli) 2004 – 2010 NIH/NHLBI
“Cardiac Sodium Channel Function regulation of permeation and gating”
The goal is to understand the mechanism role of regulation of gating of the cardiac Na channel with a focus on structural motifs in the carboxy terminus. This grant is in a no-cost extension and a competitive renewal has been submitted.
1 PO1 HL077180 (PI: Kass) Role: PI Project 2, Co-Director Core C 2004 – 2010
“Pathobiology of Cardiac Dyssynchrony and Resynchronization”
Project 2, “Electrophysiology of Cardiac Dyssynchrony and CRT”
Core C: Cell/molecular/microscopy core
The study seeks to understand the cellular and molecular basis of electrical remodeling in HF and its correction by Cardiac Resynchronization Therapy (CRT). Ventricular myocytes and wedges of myocardium will be studied for remodeling of AP characteristics, ionic currents, calcium handling and tissue properties including conduction. In Core C studies of ion channel and Ca2+ handling proteins as well as mRNA expression profiling will be performed.
R37 HL54598-11 (PI: O’Rourke) Role: Co-Investigator 1996 – 2010
“Energetic Regulation of Cardiac Ion Channels”
The major goal of this project is to determine the role of the inner membrane mitochondrial anion channel in cardiac energetics and the integrated function of the myocyte.
R01 DK072367-01 (PI: Klag) Role: Co-Investigator 2007 – 2012
“Longitudinal Study of Dialysis”
This study will allow identification of dialysis-related risk factors that are unique to persons with ESRD for arrhythmias and SCD, setting the stage for clinical trials to test therapies to prevent SCD in a high risk population. In addition, this study will provide an infrastructure to answer, in future studies, a host of important questions related to the pathogenesis of morbidity and mortality in the ESRD population.
U54 MH084691 (PI: Li) Role: Co-Investigator 2008 – 2014
NIH Johns Hopkins Ion Channel Center
This center performs high throughput screening of chemical libraries for ion channel ligands and characterizes the biophysical effects of hits on their ion channel targets.
1RC1 HL099892 (PI: Tomaselli) 2009 – 2011
NIH ARRA, “Biomarkers of Sudden Death and Heart Failure Progression”
This study will examine the role of peripheral blood mRNA and microRNA markers of SCD and HF progression in a primary prevention HF population.
Principal Investigator: Gordon Tomaselli, MD
Current Lab Members:
- Subrata Biswas, PhD Research Associate (Projects 1 and 2)
- Andreas Barth, MD, PhD Post doctoral fellow (Projects 2 and 3)
- David Edwards MD, PhD Clinical Fellow in Cardiology (Projects 1 and 2)
- Rajesh Sekar PhD, Post doctoral fellow (Projects 2 and 3)
- Darshan Dalal MD, PhD, Assistant Professor of Medicine (Project 4)
- Debbie DiSilvestre Lab Manager (Projects 1-4)
- Peihong Gao, Senior Lab Technician (Projects 1-3)
- YanLi Tian, MD, Lab Technician (Projects 1-4)
- Victoria Halperin, Lab Technician (Projects 1-4)
- Barbara Butcher, RN Coordinator PROSE-ICD (Project 4)
- Sanaz Norgard, Technician (Project 4)
- Ami Kumordzie, Undergraduate Student
- Cardiac Ion Channel structure-function and regulation
- Na, K channels
- Cellular and Molecular Remodeling in the Diseased Heart
- Heart failure and CRT
- Mechanisms of Sudden Cardiac Death
- DeMazumder D, Kass DA, O’Rourke B, Tomaselli GF. Cardiac Resynchronization therapy restores sympathovagal balance in the failing heart by differential remodeling of cholinergic signaling. Circ Res, 116:1691-9, 2015.
- Gabelli SB, Boto A, Halperin VL, Bianchet MA, Farinelli F, Aripirala S, Yoder J, Jakoncic J, Tomaselli GF, Amzel LM. Regulation of the NaV1.5 cytoplasmic domain by CaM. Nature Comm, 5:5126, 2014. (PMCID 4223872)
- Poon E, Keung W, Liang YM, Ramalingam R, Yan B, Zhang S, Chopra A, Moore J, Herren A, Lieu DK, Wong HS, Weng Z, Wong OT, Lam YW, Tomaselli GF, Chen C, Boheler KR, Li RA. Proteomic Analysis of Human Pluripotent Stem Cell-Derived, Fetal and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation. Circ: CV Gen, 8:427-36, 2015.
- Hwang CW, Johnston PV, Gerstenblith G, Weiss RG, Tomaselli GF, Bogdan VE, Panigrahi A, Leszczynska A, Xia Z. Stem cell impregnated nanofiber stent sleeve for on-stent production and intravascular delivery of paracrine factors. Biomaterials 52:318-26, 2015.
- Zhang Y, Guallar E, Blasco-Colmenares E, Nauffal V, Marine JE, Butcher B, Norgard S, Dickfeld TM, Eldadah Z, Ellenbogen KA, Tomaselli GF, Cheng A. Changes in Follow-up Left Ventricular Ejection Fraction Associated with Outcomes in Primary Prevention ICD and CRT-D Recipients. JACC 66:524, 2015. (PMCID 4522701)
- Zhang Y, Guallar E, Blasco-Colmenares E, Harms AC, Gutmann R, Vreeken RJ, Hankemeier T, Tomaselli GF, Cheng A. Serum-based oxylipins are associated with outcomes in primary prevention implantable cardioverter defibrillator patients. PLoS One 11:0157035, 2016. (PMCID 4900660)
- Tanawuttiwat T, Wagner KR, Tomaselli G, Nazarian S. Left Ventricular Dysfunction and Conduction Disturbances in Patients with Myotonic Muscular Dystrophy Type I and II. JAMA Cardiol, 2:225-8, 2017.
- Limpitikul WB, Dick IE, Tester D, Boczek NJ, Limphong P, Yang W, Choi MH, Babich J, DiSilvestre D, Kanter RJ, Tomaselli GF, Ackerman MJ, Yue D. A Precision Medicine Approach to the Rescue of Function in Malignant Calmodulinopathic Long QT Syndrome. Circ Res 120:39-48, 2017.
- Jeong MH, Kim HJ, Pyun JH, Choi KS, Lee DI, Solhjoo S, O’Rourke B, Tomaselli GF, Jeong DS, Cho H, Kang JS. Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/beta-catenin signaling. Proc Natl Acad Sci USA 114: E1345-1354, 2017. (PMCID 5338397)
- Te Riele AS, Pascual E, James CA, Leo-Macias A, Cerrone M, Zhang M, Lin X, Lin B, Sobreira NL, Amat-Alarcon N, Marsman RF, Murray B, Tichnell C, van der Heijden JF, Dooijes D, van Veen TA, Tandri H, Fowler SJ, Hauer RN, Tomaselli G, van den Berg MP, Taylor MR, Brun F, Singara G, Wilde AA, Mestroni L, Bezzina CR, Calkins H, Peter van Tintelen J, Bu L, Delmar M, Judge DP. Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovascular Res 113:102-111, 2017. (PMCID 5220677)