Research into the development, physiologic functions and disease of the cardiovascular systems. Many of the investigators listed here also belong to the Feinberg Cardiovascular Research Institute.
Labs in This Area
Role of mitochondria and metabolic processes in cancer growth, cardiac disease and metabolic disorders
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.
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.
See Dr. Ardehali's publications in PubMed.
Transcriptional regulators of inflammation and metabolism
The burgeoning epidemic of obesity and type 2 diabetes mellitus presents a major health and therapeutic challenge. Transcriptional regulation is the fundamental control mechanism for metabolism, but a gap remains in our knowledge of gene regulatory pathways that control lipid and glucose homeostasis. Thus, we seek to identify modulable pathways that may be leveraged to counteract diabetes mellitus and its comorbidities, particularly cardiovascular disease. In this effort, we use a variety of genetic, molecular, next-generation sequencing, biochemical methods and physiological models. Our recent work has helped to reveal the genomic architecture for transcriptional regulation in innate immunity, which plays a key role in both diabetes mellitus and atherosclerosis. Surprisingly, although macrophage regulatory elements are often at significant linear distance from their associated genes, we identified interplay between transcriptional activators and repressors that is highly proximate, occurring at shared nucleosomal domains (Genes & Development, 2010). Moreover, we discovered a powerful role for the BCL6 transcriptional repressor to maintain macrophage quiescence and prevent atherosclerosis (Cell Metabolism, 2012).
Currently, we are exploring the impact of activator–repressor interactions on enhancer function and transcription, the signal-dependent control of repression and the functional impact of transcriptional activators and repressors on inflammatory and metabolic disease. In particular, we strive to further understand the role for B cell lymphoma 6 (BCL6), a C2H2-type zinc finger repressor, in innate immunity and metabolism.
In related work, we are developing new methods for cell-specific isolation of RNA and chromatin from tissues composed of mixed cell populations. These genetic tools will allow us to explore transcriptional regulation in living animals with unprecedented precision and global scope using transcriptome sequencing and ChIP-sequencing. We anticipate that these approaches will identify new candidate regulators and mechanisms underlying cardiovascular and metabolic disease.
For more information, please see Dr. Barish's faculty profile.
See Dr. Barish's publications in PubMed.
Investigating the application of human induced pluripotent stem cells to study the pharmacogenomics of chemotherapy off-target toxicity and efficacy
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.
- Human induced pluripotent stem cells predict breast cancer patients’ predilection to doxorubicin-induced cardiotoxicity
- Chemically defined generation of human cardiomyocytes
- 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
See Dr. Burridge's publications on PubMed.
Contact Dr. Burridge at 312-503-4895.
Clinical Research Coordinator
Investigating the structure, function, pharmacology and molecular genetics of ion channels and channelopathies
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.
- 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.
- 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
See Dr. George's publications on PubMed.
Contact Dr. George at 312-503-4892.
The Kume Lab’s research interests focus on cardiovascular development, cardiovascular stem/progenitor cells and angiogenesis.
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.
View Dr. Kume's publications on PubMed.
For more information, visit the faculty profile for Tsutomu Kume, PhD.
Contact Dr. Kume at 312-503-0623 or the Kume Lab at 312-503-3008.
The Lin lab studies the functional significance of human-based genomic and transcriptomic discoveries in cardiometabolic and kidney diseases.
Elucidating How Genotype Lease to Phenotype in Cardiometabolic and Renal Disease
Unbiased human-based discovery efforts, such as genome-wide and exome-wide association studies, have identified many genetic loci for complex, disease-relevant traits. These genetics studies have provided invaluable data implicating novel loci in disease development and progression, but require functional follow-up to elucidate the mechanistic underpinnings driving the associated findings. A focus of the lab is to interrogate, through experimental wet-bench approaches, the functional significance of novel loci for blood lipids levels and measurements of renal function in the hopes of gaining new insights into pathways relevant to cardiometabolic and renal disease, respectively.
In particular, we are studying the role of A1CF, a gene encoding the RNA-binding protein APOBEC1 complementation factor and recently implicated as a locus for (1) elevated plasma triglycerides (Liu et al., Nature Genetics 2017), (2) estimated glomerular filtration fraction in non-diabetic individuals (Pattaro et al., Nature Communications 2016) and (3) serum urate (Kottgen et al., Nature Genetics 2013). We have already discovered that A1CF's actions extend beyond its canonical role of facilitating the editing of APOB mRNA, and we are currently integrating studies using animal and human cellular models to investigate how A1CF contributes to these associated traits.
Using iPSC and Genome Editing Technologies to Study Human Diseases
Although rodent models have contributed greatly to our understanding of human diseases, the genomic and physiologic differences between rodent and human have presented challenges in translating bench-based findings into clinic. To circumvent this roadblock, our lab is using iPSC-derived organoid models to study the effects of DNA variants within the native human genomic context. Using CRISPR-based technology to introduce or correct mutations in human iPSCs, we are modeling the effects of disease-associated mutations on cellular phenotype.
RNA-centric Approach to Studying Kidney Disease
Building upon A1CF-related work and previous experience with long non-coding RNA, we are studying the role of transcriptome-level regulation in the context of kidney disease. We have discovered that A1CF is a novel regulator of alternative splicing in both the liver and kidney, and we are currently working on how A1CF's regulation of splicing may influence intracellular metabolism. We are also studying how human-specific long non-coding RNAs influence gene expression and cellular phenotypes.
See Dr. Lin's publications in PubMed.
Cardiovascular disease epidemiology, risk estimation and prevention
Dr. Lloyd-Jones’ research interests lie in cardiovascular disease epidemiology, risk estimation and prevention. A main focus of his research has been investigation of the lifetime risks for various cardiovascular diseases and factors that modify those risks. Other areas of interest include cardiovascular disease risk estimation using novel biomarkers, imaging of subclinical atherosclerosis and the epidemiology of hypertension. His clinical and teaching interests lie in general cardiology with a focus on prevention.
For more information, visit the faculty profile of Donald Lloyd-Jones, MD, ScM.
The Martin Lab investigates the role of the skeleton in the endocrine regulation of mineral metabolism and the cardiovascular complications of mineral and bone diseases.
Our research program focuses on the contribution of the skeleton to the mineral balance in the body. Bone produces a hormone, Fibroblast Growth Factor (FGF)-23, that participates in this balance. However in mineral metabolism disorders, such as in chronic kidney disease, the massive production of FGF23 is associated with negative outcomes and mortality. By understanding the mechanisms that control the production of FGF23, our goal is to develop new therapeutic strategies and improve outcomes in mineral metabolism disorders. To this goal, we perform basic and translational research using a combination of genetics, molecular biology, proteomics, histology and advanced imaging techniques.
A major focus of the lab is to investigate the transcriptional and post-translational regulation of FGF23 within the bone cells. In particular, we study the specific role of a known regulator of FGF23, Dentin Matrix Protein 1 (DMP1), on these regulations and on osteocyte biology in the context of diseases associated with FGF23 excess (chronic kidney disease, hypophosphatemic rickets …). A second focus is to investigate the mechanisms involved in negative outcomes associated with FGF23 excess, including bone mineralization defects, cardiac hypertrophy and cognitive defects. Our team works in collaboration with the Center for Translational Metabolism and Health and the Division of Cardiology at Northwestern, and with multiple additional collaborators and partnerships around the world.
The Martin Lab is sponsored by the National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and by the Northwestern Women’s Health Research Institute.
Contact Dr. Martin at 312-503-4160 or the Martin Lab at 312-503-4805, or by email.
Genetic mechanisms responsible for inherited human diseases
My laboratory studies genetic mechanisms responsible for inherited human diseases including heart failure, cardiomyopathy, muscular dystrophy, arrhythmias, aortic aneurysms. Working with individuals and families, we are defining the genetic mutations that cause these disorders. By establishing models for these disorders, we can now begin to develop and test new therapies, including genetic correction and gene editing.
For lab information and more, see Dr. McNally's faculty profile
See Dr. McNally's publications on PubMed.
Email Dr. McNally
The Thorp laboratory studies how immune cells coordinate tissue repair and regeneration under low oxygen, such as after a heart attack.
The Edward Thorp Lab studies the crosstalk between immune cells and the cardiovascular system and, in particular, within tissues characterized by low oxygen tension or associated with dyslipidemia, such as during myocardial infarction. In vivo, the lab interrogates the function of innate immune cell phagocytes, including macrophages, as they interact with other resident parenchymal cells during tissue repair and regeneration. Within the phagocyte, the influence of hypoxia and inflammation on intercellular and intracellular signaling networks and phagocyte function are studied in molecular detail. Taken together, our approach seeks to discover and link basic molecular and physiological networks that causally regulate disease progression and in turn are amenable to strategies for the amelioration of cardiovascular disease.
View Dr. Thorp's publications at PubMed
Contact the Thorp lab at 312-503-3140.
Xin-Yi Yeap, MS
Lab Manager and Microsurgery
Plasminogen activator system in cardiovascular disease
Dr. Vaughan directs a multidisciplinary research group focused on investigating the role of the plasminogen activator system in cardiovascular disease. Active experimental programs are underway at the molecular and cellular level in animals and in humans. Transgenic and knockout mice are used in a variety of studies designed to explore the tissue-specific expression of PAI-1 in vivo and the role of the fibrinolytic system in vascular disease and tissue remodeling.
For more information visit Dr. Vaughan's faculty profile page.
View Dr. Vaughan's publications at PubMed.
The Zhao Lab studies the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury as well as endothelial and smooth muscle cell interaction in the pathogenesis of pulmonary vascular diseases.
Recovery of endothelial barrier integrity after vascular injury is vital for endothelial homeostasis and resolution of inflammation. Endothelial dysfunction plays a critical role in the initiation and progression of vascular diseases such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and atherosclerosis. A part of the research in the lab, employing genetically modified mouse models of human diseases, endothelial progenitor cells/stem cells, and translational research approach as well as nanomedicine, is to elucidate the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury and determine how aging and epigenetics regulate these processes (J. Clin. Invest. 2006, 116: 2333; J. Exp. Med. 2010, 207:1675; Circulation 2016, 133: 2447). We are also studying the role of endothelial cells in regulating macrophage functional polarization and resolving inflammatory lung injury. These studies will identify druggable targets leading to novel therapeutic strategies to activate the intrinsic endothelial regeneration program to restore endothelial barrier integrity and reverse edema formation for the prevention and treatment of ARDS in patients.
Pulmonary hypertension is a progressive disease with poor prognosis and high mortality. We are currently investigating the molecular basis underlying the pathogenesis. We have recently identified the first mouse model of pulmonary arterial hypertension (PAH) with obliterative vascular remodeling including vascular occlusion and formation of plexiform-like lesions resembling the pathology of clinical PAH (Circulation 2016, 133: 2447). Our previous studies also show the critical role of oxidative/nitrative stress in the pathogenesis of PAH as seen in patients (PNAS 2002, 99:11375; J. Clin. Invest. 2009, 119: 2009). With these unique models and lung tissue and cells from idiopathic PAH patients, we will define the molecular and cellular mechanisms underlying severe vascular remodeling and provide novel therapeutic approaches for this devastating disease.
The Zhao lab employs the state-of-the art technologies including genetic lineage tracing, genetic depletion, genetic reporter, and CRISPR-mediated in vivo genomic editing as well as patient samples to study the molecular mechanisms of acute lung injury/ARDS, and pulmonary hypertension and identify novel therapeutics for these devastating diseases. Current studies include 1) molecular mechanisms of endothelial regeneration and vascular repair following inflammatory lung injury induced by sepsis and pneumonia; 2) how aging and epigenetics regulate this process; 3) how endothelial cells regulate macrophage and neuptrophil function for resolution of inflammation and host defense; 4) stem/progenitor cells in acute lung injury and pulmonary hypertension and cell-based therapy; 5) mechanisms of obliterative pulmonary vascular remodeling; 6) molecular basis of right heart failure; 7) pathogenic role of oxidative/nitrative stress; 8) lung regeneration; 9) drug discovery; 10) nanomedicine.
View publications by Youyang Zhao in PubMed.
For more information, visit Dr. Zhao's Faculty Profile page
Email Dr. Zhao
Contact Dr. Zhao’s Lab at 773-755-6355
Zhiyu Dai, PhD.
Research Assistant Professor
Xianming Zhang, PhD.
Research Assistant Professor
Narsa Machireddy, PhD.
Research Assistant Professor
Junjie Xing, PhD.
Colin Evans, PhD.
Varsha Suresh Kumar, PhD.
Xiaojia Huang, PhD
Hua Jin, PhD
Yi Peng, PhD
Mengqi Zhu, M.S.,