Northwestern University Feinberg School of Medicine
Department of Pharmacology
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Cardiovascular Pharmacology

Cardiovascular pharmacology focuses on the fundamental mechanisms of cardiovascular cells and how drugs influence the heart and vascular system. Researchers in the department exploit novel technologies such as induced pluripotent stem cells, automated electrophysiology and genomics to investigate the causes of sudden cardiac death, congenital arrhythmias and cardiac toxicity of chemotherapeutic drugs.

Our Work

Pharmacogenomics in African-Americans

Pharmacogenomics in African-Americans and Other Understudied Populations

Minoli Perera, PharmD, PhD, associate professor of Pharmacology, studies African American pharmacogenomics, which is the study of an individual’s genome to predict how they will respond to drugs.

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Investigating the Pharmacogenomics of Chemotherapy Toxicity

Paul Burridge, PhD, assistant professor of Pharmacology, studies how a patient’s genetics cause negative responses such as cardiotoxicity to chemotherapy agents.

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Pharmacogenomics of Chemotherapy Toxicity

Cardiovascular Pharmacology Research Labs

 Hossein Ardehali Lab

Role of mitochondria and metabolic processes in cancer growth, cardiac disease and metabolic disorders

Research Description

Our lab focuses on three major areas of research:

Role of proteins involved in cellular and systemic metabolism

TTP is a protein that binds to AU-rich regions in the 3’ UTR of mRNA molecules and causes their degradation. It has been studied extensively in the field of inflammation. We recently showed that it also plays a role in cellular iron conservation. We have also shown that TTP is a key mediator of cellular metabolic processes. Our studies have demonstrated that TTP regulates glucose, fatty acid and branched-chain amino acid metabolism in the liver and muscle tissue. We also have evidence that TTP directly regulates mitochondrial electron transport chain (ETC) by targeting specific proteins in the ETC complexes. Finally, recent studies demonstrated that TTP also regulates systemic metabolism by targeting FGF-21 expression. We have both TTP Floxed mice (for the generation of tissue specific TTP knockout mice) and TTP knockout mice in the background of TNF-alpha receptor 1/2 knockout mice (to reduce the inflammatory burden).  Current studies include: 1) role of TTP in liver metabolism of fatty acids and glucose, 2) effects of TTP on mitochondrial proteins, 3) mechanism of TTP regulation of branched-chain amino acid levels and 4) role of TTP in cardiac metabolism.

Cardiac regeneration

Adult cardiomyocytes regenerate at a very low rate, but neonatal cardiomyocytes grow and replicate at a high rate. We have identified specific tandem zinc-finger (TZF) proteins that bind to mRNAs to regulate cardiac regeneration and cardiac development. Our studies suggest that these proteins may alter DNA repair in response to damage by regulating p53 and helicases. Current projects include: 1) identifying the mechanism by which TZF proteins regulate p53 and DNA damage, 2) characterization of the role of helicases in cellular proliferation and regeneration and 3) role of TZF proteins in cardiac development.

Characterization of cellular and mitochondrial iron regulation

Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), which plays a role in mitochondrial iron homeostasis and mitochondrial iron export. Mice with ABCB8 knocked out in the heart develop cardiomyopathy and mitochondrial iron accumulation. In addition, we have shown that a pathway involving mTOR and tristetraprolin, treatment with doxorubicin (an anticancer drug that also causes cardiomyopathy) and SIRT2 protein also impact cellular and/or mitochondrial iron regulation. Current studies in this area include: 1) further characterization of ABCB8 in iron homeostasis in other organs and disorders, 2) characterization of the mechanism for iron regulation by SIRT2, 3) identification of the mechanism by which mTOR is regulated by iron, 4) role of iron in viral infection, particularly HIV, 5) characterization of the effects of iron on mitochondrial dynamics and 6) identification of novel mitochondrial-specific iron chelators.

For more information, see Dr. Ardehali's faculty profile.

Publications

See Dr. Ardehali's publications in PubMed.

Contact

Dr. Ardehali

 Paul Burridge Lab

Investigating the application of human induced pluripotent stem cells to study the pharmacogenomics of chemotherapy off-target toxicity and efficacy

Research Description

The Burridge lab studies the role of the genome in influencing drug responses, known as pharmacogenomics or personalized medicine. Our major model is human induced pluripotent stem cells (hiPSC), generated from patient's blood or skin. We use a combination of next generation sequencing, automation and robotics, high-throughput drug screening, high-content imaging, tissue engineering, electrophysiological and physiological testing to better understand the mechanisms of drug response and action.

Our major effort has been related to patient-specific responses to chemotherapy agents. We ask the question: what is the genetic reason why some patients have a minimal side effects to their cancer treatment, whilst others have encounter highly detrimental side-effects? These side-effects  can include cardiomyopathy (heart failure or arrhythmias), peripheral neuropathy,  or hepatotoxicity (liver failure). It is our aim to add to risk-based screening by functionally validating genetic changes that predispose a patient to a specific drug response.

Recent Findings

  • Human induced pluripotent stem cells predict breast cancer patients’ predilection to doxorubicin-induced cardiotoxicity
  • Chemically defined generation of human cardiomyocytes

Current Projects

  • Modeling the role of the genome in doxorubicin-induced cardiotoxicity using hiPSC
  • Investigating the pharmacogenomics of tyrosine kinase inhibitor cardiotoxicity
  • hiPSC reprogramming, culture and differentiation techniques
  • High-throughput and high-content methodologies in hiPSC-based screening

For lab information and more, see Dr. Burridge’s faculty profile and lab website.

Publications

See Dr. Burridge's publications on PubMed.

Contact

Contact Dr. Burridge at 312-503-4895.

Lab Staff

Postdoctoral Fellows

Zhengxin Jiang, Tarek Mohamed, Adam Schuldt

Clinical Research Coordinator

Mohammed Nooruddin

Graduate Students

K. Ashley Fetterman, Michael Orman, Marisol Tejeda

Technical Staff

Defne Egecioglu, Hui-Hsuan Kuo

 Al George Lab

Investigating the structure, function, pharmacology and molecular genetics of ion channels and channelopathies

George Lab

Research Description

Ion channels are ubiquitous membrane proteins that serve a variety of important physiological functions, provide targets for many types of pharmacological agents and are encoded by genes that can be the basis for inherited diseases affecting the heart, skeletal muscle and nervous system.

Dr. George's research program is focused on the structure, function, pharmacology and molecular genetics of ion channels. He is an internationally recognized leader in the field of channelopathies based on his important discoveries on inherited muscle disorders (periodic paralysis, myotonia), inherited cardiac arrhythmias (congenital long-QT syndrome) and genetic epilepsies. Dr. George’s laboratory was first to determine the functional consequences of a human cardiac sodium channel mutation associated with an inherited cardiac arrhythmia. His group has elucidated the functional and molecular consequences of several brain sodium channel mutations that cause various familial epilepsies and an inherited form of migraine. These finding have motivated pharmacological studies designed to find compounds that suppress aberrant functional behaviors caused by mutations.

Recent Findings

  • Discovery of novel, de novo mutations in human calmodulin genes responsible for early onset, life threatening cardiac arrhythmias in infants and elucidation of the biochemical and physiological consequences of the mutations.
  • Demonstration that a novel sodium channel blocker capable of preferential inhibition of persistent sodium current has potent antiepileptic effects.
  • Elucidation of the biophysical mechanism responsible for G-protein activation of a human voltage-gated sodium channel (NaV1.9) involved in pain perception.

Current Projects

  • Investigating the functional and physiological consequences of human voltage-gated sodium channel mutations responsible for either congenital cardiac arrhythmias or epilepsy.
  • Evaluating the efficacy and pharmacology of novel sodium channel blockers in mouse models of human genetic epilepsies.
  • Implementing high throughput technologies for studying genetic variability in drug metabolism.
  • Implementing automated electrophysiology as a screening platform for ion channels.

For lab information and more, see Dr. George’s faculty profile.

Publications

See Dr. George's publications on PubMed.

Contact

Contact Dr. George at 312-503-4892.

Lab Staff

Research Faculty

Lynn DoglioVladimir Jovasevic, Irawati Kandela, Andrew Mazar, Franck PotetMegan Roy-PuckelwartzChristopher Thompson, Carlos Vanoye

Senior Researchers

Reshma Desai, Jean-Marc DekeyserPaula FriedmanChristine Simmons

Lab Manager

Tatiana Abramova

Postdoctoral Fellows

Thomas HolmDina Simkin

Medical Resident

Tracy Gertler

Graduate Students

Surobhi Ganguly, Lisa Wren

Technical Staff

Shannon Gallagher

 Tsutomu Kume Lab

The Kume Lab’s research interests focus on cardiovascular development, cardiovascular stem/progenitor cells and angiogenesis.

Research Description

Cardiovascular development is at the center of all the work that goes on in the Kume lab. The cardiovascular system is the first functional unit to form during embryonic development and is essential for the growth and nurturing of other developing organs. Failure to form the cardiovascular system often leads to embryonic lethality and inherited disorders of the cardiovascular system are quite common in humans. The causes and underlying developmental mechanisms of these disorders, however, are poorly understood. A particular emphasis in our laboratory has recently been the study of cardiovascular signaling pathways and transcriptional regulation in physiological and pathological settings using mice as animal models, as well as embryonic stem (ES) cells as an in vitro differentiation system. The ultimate goal of our research is to provide new insights into the mechanisms that lead to the development of therapeutic strategies designed to treat clinically relevant conditions of pathological neovascularization.

Publications

View Dr. Kume's publications on PubMed.

For more information, visit the faculty profile for Tsutomu Kume, PhD.

Contact Us

Contact Dr. Kume at 312-503-0623 or the Kume Lab at 312-503-3008.

Staff Listing

Austin Culver
MD Candidate
312-503-3008

Anees Fatima
Research Assistant Professor
312-503-0554

Christine Elizabeth Kamide
Senior Research Technologist
312-503-1446

Erin Lambers
PhD Candidate
312-503-5652

Ting Liu
Senior Research Technologist
312-503-3008

Jonathon Misch
Research Technologist
312-503-6153

 Minoli Perera Lab

Pharmacogenomics research in minority patient populations

Perera Lab

Research Description

The Perera laboratory focuses on pharmacogenomics (using a patient's genome to predict drug response) in minority populations. Working in this translation research space requires both clinical expertise as well as the use of high-throughput basic science approaches. Our goal is to bring the benefits of precision medicine to all US populations.

The Perera lab has recruited patient populations from around the world. The data collection includes genomic (DNA), transcriptomic (mRNA), pharmacokinetic and clinical data. We then integrate these different data sources to understand genetic drivers of drug response (e.g. genetic predictors of adverse events) as well as disease. By studying minority populations the lab has discovered genetic risk variants that may benefit the implementation of precision medicine in African Americans and others.

Recent Findings

  • Warfarin Bleeding Risk Association study
    We recently discovered a genetic variant that predispose African Americans to bleeding complications while on anticoagulant drugs. These bleeds occurred even when the patient was within the therapeutic window for the medication. We hope that this new data will help to identify high risk individuals prior to therapy.
  • Novel African-specific genetic polymorphisms predict the risk of venous thromboembolism
    We discovered a new genetic variant associated with a 2.5 fold increase in risk of developing a blood clot. We went on to show that this SNP significantly affects the expression of a key protein in the coagulation cascade. View article on PubMed. Read press release.
  • Common genetic variant is predictive of warfarin metabolism and gene expression in African Americans
    We tested the association of a SNP, previously shown to effect gene expression CYP2C9, for association with warfarin drug clearance (pharmacokinetics). This SNP increased the expression of CYP2C9 (enzyme that metabolized warfarin), hence causing fast clearance of the drug. This African American-specific SNP may help to explain the higher warfarin dose required by African Americans in general. View article on PubMed.

Current Projects

  • Genomics of Drug Metabolism
    We are using African America primary hepatocytes to understand the genetic regulation of drug metabolizing enzymes that are involved in a majority of drug used in the US.
  • Anticoagulant Pharmacogenomics
    We are conducting several genetic association studies to understand both the genetic drivers and the biological mechanisms behind response and adverse effect to anticoagulant medications.
  • Pharmacogenomics of Inflammatory Bowel disease
    We are investigating the genetic predictors of primary non-response to biologic therapies used in inflammatory bowel disease. Studies have implication for other autoimmune disorders that target the same pathways.
  • eMERGE
    We are involved in analyzing the GWAS and sequencing data specifically for genomics variation affect key pharmacogenomics gene in African Americans.

For lab information and more, see Dr. Perera's faculty profile and lab website.

Publications

See Dr. Perera's publications on PubMed.

Contact

Contact Dr. Perera at 312-503-6188 or the lab at 312-503-4119.

Lab Staff

Postdoctoral Fellows

Tanima De, Paula Friedman

Lab Manager

Cristina Alarcon

Graduate Student

Yizhen Zhong 

 Lisa Wilsbacher Lab

The Wilsbacher Lab investigates the roles of G protein-coupled receptors in heart development and disease.

Dr. Wilsbacher's research focuses on cardiac development and cardiomyocyte maintenance in the setting of pathological stress. Currently, the laboratory investigates the G protein-coupled receptor sphingosine-1-phosphate receptor 1 (S1P1) and its unexpected role in cardiomyocyte proliferation and cardiac development. Dr. Wilsbacher’s research aims to identify the signaling mechanisms that underlie these cardiac developmental effects and their potential roles in congenital heart disease. In addition, the laboratory explores whether and how S1P1 signaling contributes to cardiac remodeling in the adult heart, particularly in the setting of cardiac fibrosis.

Publications

View lab publications via PubMed.

For more information, visit Dr. Wilsbacher's faculty profile or visit the Lisa Wilsbacher Lab Site.

Contact Us

Contact Dr. Wilsbacher at 312-503-6880 or the Wilsbacher Lab at 312-503-5309.

Lab Staff

Jayne Wolfe
Research Technologist II
312-503-5309

Bisheng Zhou
Postdoctoral Fellow
312-503-5309

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