Our lab studies the role of the hERG potassium channel and its critical roles in human electrical signaling. We use cell lines differentiated from pluripotent stem cells to link fundamental observations of hERG channel biophysics with human physiology and pathophysiology. Our work seeks to define new mechanisms of disease, with the long-term goal of developing novel therapies to improve clinical care.
hERG as a Therapeutic Target for Cardiac Electrical Disorders
The human ether-a-go-go gene (hERG) encodes the voltage gated potassium channel that conducts the cardiac repolarizing current IKr. Impaired repolarization from reduced IKr increases the risk of potentially lethal ventricular arrhythmias and is a hallmark of long QT syndrome (LQTS) and heart failure. Treatments for impaired repolarization are limited largely due to their high incidence of off-target effects. hERG cytoplasmic domains interact to negatively modulate IKr, making them potential targets to treat diseases of repolarization.
Our earlier work showed that antibody peptide fragments targeting distinct regions of the cytoplasmic hERG Per-Arnt-Sim (PAS) domain selectively increase IKr and shorten action potential duration (APD). As a therapeutic, such fragments would potentially shorten APD and restore impaired repolarization in LQTS and heart failure. Additionally, antibody fragments directed toward the PAS and other domains would be useful tools to characterize how specific gating processes regulate cellular behavior and overall cardiac physiology.
We are now characterizing the anti-arrhythmic effects of these antibodies on healthy human stem cell-derived cardiomyocytes (iPSC-CMs) and iPSC-CMs obtained from LQTS patients. These experiments will generate novel tools to probe the mechanistic role of distinct channel processes in native physiology. Additionally, these experiments will act as a proof-of-concept for future experiments designed to develop anti-hERG antibody fragments into treatments for impaired repolarization. The image depicts an iPSC-CM monolayer with hERG in orange, Actin in blue, and the nucleus in magenta.
hERG1 Dysfunction in Fetal and Neonatal Sudden Cardiac Death
The incidence of sudden cardiac death is six times greater in the first year of life compared to any other period during childhood or adolescence, but data on the fundamental aspects of electrophysiology in the young heart are limited. Our long-term goal is to understand the mechanistic relationship between ion channel regulation and susceptibility to arrhythmia during early cardiac development and maturation. hERG, encoded by KCNH2, is a developmentally regulated potassium channel that conducts the cardiac repolarizing current, IKr. Reduced IKr increases the likelihood of sudden cardiac death, but the mechanisms of arrhythmia appear to differ in fetal, neonatal, and adult hearts. Specifically, how variants in KCNH2 trigger sudden cardiac death in the immature heart is not clear. There is therefore a critical unmet clinical need to define the mechanistic link between developmental regulation of the hERG potassium channel and arrhythmia in the immature human heart. By doing so, physicians will be better equipped to predict the potentially lethal consequences of KCNH2 variants in the earliest stages of life.
Our work in this area has demonstrated that cardiac maturation shifts hERG subunit mRNA and protein abundance, modifying both IKr magnitude and IKr kinetics. We are now using gene-edited cardiomyocytes and targeted RNA interference to define the subunit specific regulators of hERG transcription through cardiac maturation. We are also using stem cell-derived cardiomyocytes, acutely isolated rabbit myocytes, and Langendorf-perfused rabbit heart to define the contribution of hERG subunit abundance on cardiac pharmacology and arrhythmia in the immature heart. These data will improve the capacity of physicians to predict the potential effects of pharmacological therapies on the immature heart, and predict the pathogenicity of KCNH2 variants in fetal and neonatal myocardia.
Pluripotent Stem Cell-Derived Neurons to Model the Human Brain
Patients with disorders of cardiac electrical signaling also display a relatively a high incidence of seizure and epilepsy. The molecular mechanisms that link electrical dysfunction at the heart with electrical dysfunction in the brain are poorly understood. Stem cell-derived cells lines represent a uniquely accessible tool to explore the overlapping genetic and molecular regulators of neuronal and cardiac excitability. We are using our expertise in stem cell differentiation in combination with techniques in CRISPR gene editing to identify co-regulators of the brain-heart electrical axis.
Professor George Michael Deeb, MD, instructs students on the anatomy and proper suture technique in the mammalian heart.
Since 2022 the Frankel Cardiovascular Center DEI & Wellbeing Steering Committee has partnered with Cody High School to provide a year-long science program for students in 9th, 10th, and 11th grades. The goal of this program is to promote diversity, equity, and inclusion in the STEM and healthcare fields.
Throughout the academic year the program provides monthly “Lunch and Learn” sessions at Cody High. Each month, scientific and medical professionals from Michigan Medicine provide interactive lectures on a range of cardiovascular health related topics. In May the program culminates with a week-long camp at the Frankel Cardiovascular Center Campus in Ann Arbor. Throughout the week, the students meet and network with a variety of healthcare and research professionals from all levels of Michigan Medicine. They participate in hands-on professionally-led medical demonstrations, one-on-one discussions with research and medical professionals, and complete daily small group job shadowing. Through these activities the students learn about the many exciting careers in cardiovascular science, medicine, and healthcare
The 2023 Class takes in the sun following a tour and discussion with Michigan’s Survival Flight Staff.
For additional information or to volunteer please contact:
Dave Jones
davekj@med.umich.edu
Joi Rencher
jrencher@med.umich.edu
This program is made possible by the volunteer efforts from countless Faculty and Staff from both Cody High School and Michigan Medicine and a Frankel Cardiovascular Center Inaugural Grant.
Dave Jones, Ph.D.
Principle Investigator
Assistant Professor Department of Pharmacology
Assistant Professor Department of Internal Medicine
Co-Chair FCVC DEI & Well-Being Steering Committee
davekj@med.umich.edu
Abhilasha Jain, M.Sc.
Lab Manager
jainab@med.umich.edu
Eric Jimenez-Vazquez, Ph.D.
Research Investigator
jimenezv@med.umich.edu
Francisco Sanchez-Conde, B.Sc.
Ph.D. Candidate
fransanc@med.umich.edu
Charlie Martin
Dogter of Philosophy
Olivia Stack
Senior Undergraduate Research Technician
ostack@umich.edu
Matthew Goodrich
Senior Undergraduate Research Technician
gmatty@umich.edu
Hannah Harmes
Undergraduate Research Technician
hharmes@umich.edu
Pamela Ruzycki
UROP Fellow
pruzycki@umich.edu
Diamond Thomas, M.Sc.
Clinical Subject Associate at C. S. Mott Children’s Hospital
diamonthom@umich.edu
Chiamaka Ukachukwu, Ph.D.
Advisor at Eli Lilly
ugochi@umich.edu
D.K. Jones*, A.A. Johnson*, E.C. Roti Roti*, F. Liu, R. Uelmen, R. A. Ayers, I. Baczko, D. J. Tester, M. J. Ackerman, M.C. Trudeau, G.A. Robertson. 2018 Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG proteins in the heart. J Cell Sci. Mar 5. * Indicates shared first authorship.
C. Harley*, G.S. Starek*, D.K. Jones*, A.S. Fernandes, G.A. Robertson, J. Cabral. 2016. Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain. PNAS. Aug 30; 113(35): 9916-21. * Indicates shared first authorship.
Liu, F., D.K. Jones, W. J. de Lange, G.A. Robertson. 2016. Co-translational association of mRNA encoding subunits of heteromeric ion channels. PNAS. Apr 26; 113(17):4859-64.
D.K. Jones, F. Liu, N. Dombrowski, S. Joshi, G.A. Robertson. 2016. Dominant negative consequences of a hERG 1b mutation associated with intrauterine fetal death. Prog Biophys Mol Bio. Jan; 120(1-3):67-76.
D.K. Jones, F. Liu, R. Vaidyanathan, L.L. Eckhardt, M.C. Trudeau, G.A. Robertson. 2014. hERG 1b is critical for human cardiac repolarization. PNAS. Dec 16; 111(50): 18073-7.
D.K. Jones, T.C. Claydon, P.C. Ruben. 2013. Extracellular protons inhibit charge immobilization in the cardiac voltage-gated sodium channel. Biophysical. July 2; 105(1): 101-107.
D.K. Jones, C.H. Peters, C.R. Allard, T.C. Claydon, P.C. Ruben. 2013. Proton sensors in the pore domain of the cardiac voltage-gated sodium channel. J Biol Chem. Feb 15; 288(7): 4782-91.
D.K. Jones, S.A. Tolhurst, T.C. Claydon, P.C. Ruben. 2011. Extracellular proton modulation of the cardiac voltage-gated sodium channel, NaV1.5. Biophysical. Nov 2; 101(9): 2147-56.
D.K. Jones, S.A. Tolhurst, T.C. Claydon, P.C. Ruben. 2011. Extracellular proton modulation of the cardiac voltage-gated sodium channel, NaV1.5. Biophysical. Nov 2; 101(9): 2147-56.
Lee, C.H., D.K. Jones, C. Ahern, M.F. Sarhan, P.C. Ruben. 2010. The biophysical costs associated with tetrodotoxin resistance in the garter snake, Thamnophis sirtalis. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. Jan; 197(1): 33-43.
D.K. Jones, and P.C. Ruben. 2008. Biophysical defects in voltage-gated sodium channels associated with long QT and Brugada syndromes. Channels. Mar-Apr; 2(2): 70-80.
Postdoctoral Fellows
The Jones lab is not currently seeking a Postdoc.
Ph.D. Students
The Jones lab accepts rotation students, year round. Please contact Dave directly at davekj@umich.edu for more information.
M.Sc. Students
The Jones lab accepts Master’s students every fall. If interested, you can email Dave Jones, or contact the Director of our department’s M.Sc. program, Steve Fisher for more information.
Undergraduates
The Jones lab is currently accepting applications for undergraduate research fellows to begin in the fall semester. Prospective students should email their CV and transcript to Dave Jones,
Staff
There are currently no open staff positions.