Research into the genetic basis of human diseases.
Labs in This Area
Estrogen metabolism in breast cancer, endometriosis, and uterine fibroids
The laboratory research of Serdar E. Bulun, MD, focuses on studying estrogen biosynthesis and metabolism, in particular aromatase expression, in hormone-dependent human diseases such as breast cancer, endometriosis and uterine fibroids.
A team of investigators works on understanding the epithelial-stromal interactions and aromotase overexpression in breast cancer tissue. Because aromatase inhibitors treat breast tumors primarily via suppressing intratumoral estrogen biosynthesis, these efforts are important for discovering new targets of treatment.
Another team studies endometriosis. Basic data from this laboratory led to the introduction of aromatase inhibitors into endometriosis treatment. Human tissues and a primate model are used to elucidate cellular and molecular mechanisms responsible for the development of endometriosis.
Regulation of aromatase expression is also studied in uterine fibroids, benign tumors that are dependent on estrogen for growth, by a third team.
A fourth team is investigating the link between progesterone action and estrogen inactivation in normal endometrium and endometriosis.
Lastly, a fifth team has identified novel mutations that cause familial excessive estrogen formation syndrome. This syndrome is characterized by short stature, gynecomastia, and hypogandism in males and early breast development and irregular menses in females. In this syndrome, heterozygous inversions in chromosome 15q21, which cause the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in estrogen excess owing to the overexpression of aromatase in many tissues.
For more information, please see Dr. Bulun's faculty profile.
See Dr. Bulun'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.
Studying molecular motors and cell motility
Movement is a fundamental characteristic of life. Cell movement is critical for normal embryogenesis, tissue formation, wound healing and defense against infection. It is also an important factor in diseases such as cancer metastasis and birth defects. Movement of components within cells is necessary for mitosis, hormone secretion, phagocytosis and endocytosis. Molecular motors that move along microfilaments (myosin) and microtubules (dynein) power these movements. Our goal is to understand how these motors produce movement and are regulated. We wish to define their involvement in intracellular, cellular, and tissue function and disease—with the long-term goal of developing therapies for the treatment of diseases caused by defects in these molecular motors.
Our work involves the manipulation of myosin and dynein function in the single celled eukaryote Dictyostelium, cultured mammalian cells and transgenic and knockout mice. Yeast two-hybrid screens to identify proteins that interact with or regulate myosin and dynein and characterization of gene expression are being used to define the pathways regulating myosin and dynein. To analyze the biological significance of myosin and dynein, we use confocal and digital microscopy of living cells, analysis of cell movement, vesicle transport and cell division. We employ biochemical techniques including heterologous expression, enzyme purification and characterization, and analysis of how phosphorylation state affects physiological function. We are pursuing signal transduction studies to understand the physiologically important pathways that regulate cell motility and biophysical studies such as in vitro motility assays to understand how these molecular motors function at the molecular level.
See Dr. Chisholm's publications on PubMed.
Contact Dr. Chisholm at 312-503-3209.
Genetic and molecular basis of Polycystic ovary syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is the most common cause of both hormonal-related infertility and oligomenorrhea. This syndrome is characterized by increased androgen biosynthesis and disordered gonadotropin secretion. PCOS is also associated with profound insulin resistance and increased risk for type 2 diabetes. PCOS, and the insulin resistance associated with it, appear to be genetic defects. Moreover, insulin resistance plays a causal role in the abnormalities of ovarian steroidogenesis as well as the anovulation characteristic of PCOS. There are three major research projects currently ongoing, ranging from large-scale family studies through intensive patient-oriented research to animal models and cellular and molecular biology.
The Genetic Basis of PCOS
This research program focuses on identifying the susceptibility genes for PCOS, performing genotype-phenotype analyses and identifying environmental and genetic factors contributing to PCOS familial phenotypes. Studies include family studies with linkage analysis and detailed analyses of reproductive function and insulin action in women with PCOS and their relatives. The approaches include statistical genetics and in vivo studies of insulin action and secretion, as well as pulsatile gonadotropin secretion. One susceptibility gene region has been identified on chromosome 19p13.2 close to the insulin receptor gene. This research is supported by the NIH-NICHD National Cooperative Program for Infertility Research.
Insulin Action and Secretion in PCOS
These studies are focused on identifying the cellular and molecular mechanisms of defects in insulin action and secretion in PCOS. Approaches include detailed in vivo studies of these parameters utilizing techniques such as the euglycemic glucose clamp, frequently sampled intravenous glucose intolerance test with minimal model analysis and graded glucose infusions. Insulin receptor signal transduction is examined in human skeletal muscle biopsies, as well as in human skeletal muscle and adipocyte cultures. Intrinsic defects in insulin receptor signaling have been identified and the mechanisms of these abnormalities are currently under investigation. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Fetal Origins of PCOS
These studies examine the impact of prenatal androgen exposure on insulin action in rodent, primate and sheep models. Studies include examination of lipolysis and insulin signaling in skeletal muscle and adipose tissue and the molecular mechanism of fetal programming. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Scholars will have the opportunity to become involved in phenotype-genotype studies of PCOS families with a strong exposure to the genetics of complex diseases.
For more information, please see Dr. Dunaif's faculty profile.
See Dr. Dunaif's publications in PubMed.
Investigating cell and molecular mechanisms of cerebral cortical development.
The Feng lab is interested in the cellular and molecular mechanisms that control the developmental formation of the cerebral cortex. Our research is specifically focused on understanding how neural progenitors produce an enormous quantity and diversity of cortical during embryonic development and how abnormalities of neural progenitors lead to cortical malformations and neuropsychiatric disorders. We take advantage of human genetic mutations that are known to cause severe anatomical and functional deficits of the cerebral cortex, combining mouse genetic models of these human mutations with cell biology approaches to delineate the molecular mechanisms of developmental neurogenesis. Current research topics include neural progenitor cytoarchitecture maintenance, signal transduction, cell cycle regulation, and cell fate determination. We would like to learn how these cellular processes are interconnected spatiotemporally to govern the generation of diversified cortical neurons in normal and diseased conditions.
For more information, see Dr. Feng's faculty profile.
View Dr. Feng's full list of publications on PubMed.
Yuanyi Feng, PhD at 312-503-1046
Shauna L. Houlihan
Alison A. Lanctot
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.
Investigating the genetic basis of epilepsy
My research program is focused on studying the genetic basis of epilepsy, a common neurological disorder that affects approximately 1% of the population. Epilepsy is thought to have a genetic basis in approximately two-thirds of patients, including a small fraction caused by single gene mutations. Many genes responsible for rare, monogenic epilepsy have been identified. The genes identified are components of neuronal signaling, including voltage-gated ion channels, neurotransmitter receptors, ion-channel associated proteins and synaptic proteins. We use mouse models with mutations in ion channel genes to understand the underlying molecular basis of epilepsy and to identify modifier genes that influence phenotype severity by modifying disease risk. Identifying genes that influence epilepsy risk improves our understanding of the underlying pathophysiology and suggests novel targets for therapeutic intervention.
For lab information and more, see Dr. Kearney's faculty profile.
See Dr. Kearney's publications on PubMed.
Contact Dr. Kearney at 312-503-4894.
The Kelleher Group has three primary lines of research focused on Top Down Proteomics, Natural Products Discovery and Biosynthesis and Chromatin Oncobiology and DNA-Damage. An underlying focus, driving all lines of research, is our continued push towards optimizing instrumentation and bioinformatic approaches to best suit the unique needs of a Top Down analysis.
The main focus for our Top Down Proteomics subgroup is to push the limits for whole proteome analysis of mammalian cells, striving for a future in which Top Down analysis rivals that of Bottom Up in the number of protein identifications per run. Recently we have seen progress towards this very goal with the introduction of a separation platform specifically designed to minimize the most common problem in Top Down Proteomics, intact protein separations. This platform effectively reduces sample complexity and separates proteins depending on size, resulting in an opportunity for the researcher to select the optimal analysis method for the sample.
Our Natural Products subgroup is focused on the discovery and biosynthesis of novel natural products. Developments from this subgroup include the introduction of the PrISM platform, geared towards the identification of natural products synthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) without prior knowledge of a gene sequence. This is made possible by our ability to detect a phosphopantetheinyl (Ppant) ejection marker ion for NRPS/PKS thiolation domains. We also work in collaboration with groups from other universities to provide mass spectrometry analysis of novel biochemical systems.
We also have a long-standing interest in histone analysis. Our Chromatin Oncobiology and DNA-Damage subgroup continues to dig deeper into the "histone code", a complex mixture of post-translational modifications that together determine a host of cellular processes. We are interested in visualizing dynamic histone PTM changes simultaneously on multiple sites. Through application of technology developed in our Top Down Proteomics subgroup, we are able to apply "Precision Proteomics" to histone analysis.
View lab publications via PubMed.
Contact the Kelleher Lab at 847-467-1086 or 847-467-4362
Molecular genetics of thyroid and other endocrine disorders
Dr. Kopp's research focuses on various forms of thyroid disease. Principal areas of interests are the molecular genetics of congenital hypothyroidism and Pendred's syndrome. Pendred's syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goiter and impaired iodide organification. It is caused by mutations in the PDS (Pendred syndrome) gene that encodes pendrin, an anion transporter belonging to the solute carrier family 26A (SCL26A).
Other areas of active research include the molecular genetics of endocrine diseases, such as neurohypophyseal and nephrogenic diabetes insipidus, and the analysis of polymorphisms in genes involved in androgen metabolism in order to define determinants of steroid hormones and prostate cancer risk in men.
Functional characterization of pendrin
Molecular genetics of congenital hypothyroidism
Genetic factors determining androgen levels
For more information, please see Dr. Kopp's faculty profile.
See Dr. Kopp's publications in PubMed.
Genetic determinants of maternal metabolism and fetal growth
A major interest of the Lowe laboratory is genetic determinants of maternal metabolism during pregnancy and the interaction between the intrauterine environment and genetics in determining size at birth. This interest is being addressed using DNA and phenotype information from ~16,000 mothers and their babies who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. A genome wide association study using DNA from mothers and babies from four different ancestry groups has been performed, with several different loci demonstrating genome-wide significant association with maternal and fetal traits. Replication studies have confirmed the identified associations. Studies are now underway now to identify the causal variants and their functional impact. In related studies performed with investigators at Duke, targeted and untargeted metabolomic studies are underway to determine whether metabolic signatures characteristic of maternal obesity and/or hyperglycemia can be identified in mothers and babies. Integration of metabolomic and genomic data is also planned to more fully characterize maternal metabolism during pregnancy and its interaction with fetal growth. Finally, a HAPO Follow-Up Study has been initiated in which a subset of the HAPO mothers and babies (now 8-12 years of age) will be recruited to examine the hypothesis that maternal glucose levels during pregnancy are positively correlated with metabolic measures in childhood, including adiposity, lipidemia, glycemia, and blood pressure.
For further information visit Dr. Lowe's faculty profile page
View Dr. Lowe's publications at PubMed
Regulation of Motor Neuron and Dopaminergic Neuron Function in Development and Disease
Postdoctoral fellow jobs and graduate student rotation projects are available.
Research DescriptionSpinal Motor Neurons and Spinal Muscular Atrophy (SMA)
SMA is characterized by the selective degeneration of spinal motor neurons. As the leading genetic cause of infant mortality, SMA affects one in every eight thousand live births. Our group is interested in studying mechanism regulating motor neuron development and function, as well as why motor neurons specifically degenerate in SMA. To address these questions, we use a combination of genetic, biochemical and cell biological approaches, and utilize genetically modified mice, induced pluripotent stem (iPS) cells reprogrammed from fibroblasts, and zebrafish as model systems. We focus on the regulation of mitochondrial functions in SMA pathogenesis. Based on our findings, we hope to develop new therapeutic strategies for treating SMA.
Dopaminergic Neurons and Parkinson's Disease
Dopaminergic neurons located in the ventral midbrain control movement, emotional behavior and reward mechanisms. Dysfunction of these neurons is implicated in Parkinson’s disease, drug addiction, depression and schizophrenia. Our group is interested in the genetic and epigenetic mechanisms regulating dopaminergic neuron functions in disease and aging conditions. We are particularly interested in how aging and mitochondrial oxidative stress contribute to dopaminergic neuron degeneration in Parkinson's disease through transcriptional and epigenetic regulations. We use mouse models, cultured neurons and iPS cells for these studies.
View Dr. Ma's publications at PubMed
Nimrod Miller, PhD, Postdoctoral Fellow
Han Shi, Graduate Student
Brittany Edens, Graduate Student
Kevin Park, Graduate Student
Monica Yang, Undergraduate Student
Aaron Zelikovich, Undergraduate Student
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
Pharmacogenomics research in minority patient populations
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 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.
- 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.
- 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.
We are involved in analyzing the GWAS and sequencing data specifically for genomics variation affect key pharmacogenomics gene in African Americans.
See Dr. Perera's publications on PubMed.
Contact Dr. Perera at 312-503-6118 or the lab at 312-503-4119.
We are working to discover causes, understand mechanisms of disease and develop cell and animals model in order to develop rational therapies for neurogenetic and neurodegenerative disorders.
Laboratory of Neurogenetics and Neuromuscular Medicine
Our research laboratory is working to determine the causes of and treatments for neurodegenerative disorders and those that affect the muscle, the neuromuscular junction, peripheral nerves and central control of these systems. in particularly those that involve mitochondria , and those that involve motor neuron function, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia and ALS (ALS/FTD), primary lateral sclerosis (PLS), the hereditary spastic parapareses (HSP), and related disorders. Recently we have discovered novel genetic causes of Parkinson Disease. This laboratory has pioneered the gene discovery approach to ALS and related disorders, engineered the first mouse model, and have since identified basic molecular mechanisms of pathology in ALS and ALS/dementia on which rational therapy can be now based.
For more information see the faculty profile of Teepu Siddique, MD.
View Dr. Siddique's full list of publications at PubMed.
Teepu Siddique, MD at 312-503-4737
Research Lab Manager and Neuromuscular Laboratory Clinical Supervisor
Research Technicians II
Senior Research Technicians
Senior Research Nurse
Susceptibility genes for complex diseases
Dr. Urbanek’s research focuses on the identification of susceptibility genes for complex diseases. Her approach to this research is to use family-based gene-mapping techniques and population-based association studies in conjunction with molecular techniques to identify and verify genes and pathways contributing to the pathogenesis of genetically complex diseases. Specifically, she is carrying out studies to identify susceptibility genes for polycystic ovary syndrome (PCOS) that map to Chr19p3.13. She has previously shown that this region shows linkage and association with PCOS in a large set of families. Other projects focus on identifying candidate genes for gestational diabetes and glycemic control during pregnancy and identifying genetic variation contributing to extreme obesity
Identification of sequence variants in PCOS candidate genes
Identification of candidate genes for contributing glycemic control during pregnancy and to gestational diabetes
Genetic variation contributing to extreme obesity
Linkage and family-based association studies
Genome-wide association studies
For more information, visit Dr. Urbanek's faculty profile page.
View Dr. Urbanek's publications at PubMed.
Computational immunology - Using genomic approaches to study rheumatic disease.
The goal of the Winter Lab of Functional Genomics is to apply genomic approaches to study rheumatic disease. Led by Dr. Deborah Winter, a computational immunologist, we employ the latest technologies for assays – such as RNA-seq, ChIP-seq, ATAC-seq, and single cell expression – to profile the transcriptional and epigenomic profiles of immune cells in health and disease. Our goal is to define the underlying regulatory networks and understanding how they respond to challenge, illness, and injury. We are particularly interested in the role of macrophages in diseases such as scleroderma, rheumatoid arthritis, and lupus. Previous research has addressed the impact of the tissue environment on resident macrophages and the role of microglia, CNS-resident macrophages, in brain development. Our research combines molecular and systems biology, biotechnology, clinical applications, and computer science. We use both mouse models and patient samples to help us understand and test different systems. We are committed to high standards of analysis and are continually updating and training in innovative computational techniques. We are currently recruiting highly motivated individuals to join the lab.
For more information, visit the faculty profile of Dr. Winter.
View Dr. Winter's publications at PubMed
Contact Dr. Winter at 312-503-0535 or by email.
Genetics and epigenetics of complex traits including risks for common diseases and drug response
For more information, visit Dr. Zhang's Faculty Profile page.