This page lists the Ken & Ruth Davee Department of Neurology research groups by principal investigator. Learn about the broader goals for study within the research groups, as well as details on individual faculty labs and teams.
Investigating dopamine neurogenesis and subtypes; studying the role of microRNAs in Schwann cell (SC) differentiation.
Topic 1. Mechanisms underlying dopamine neurogenesis
The floor plate, the ventral organizing center in the embryonic neural tube, patterns the neural tube by secreting the potent morphogen Shh. Using genetic fate mapping, we have recently shown that the midbrain floor plate, unlike the hindbrain and spinal cord floor plate, is neurogenic and is the source of midbrain dopamine neurons (Joksimovic, et al, 2009 Nature Neuroscience, Joksimovic et al. 2009 PNAS). We are interested in understanding pathways that are involved in floor plate neurogenesis and production of dopamine neurons. We have shown that Wnt signaling is critical for the establishment of the dopamine progenitor pool and that miRNAs may modulate the dosage and timing of the Wnt pathway (Anderegg et al, PloS Genetics 2013).
Topic 2. Deconstructing Dopaminergic Diversity
The neurotransmitter dopamine, produced mainly by midbrain dopaminergic neurons, influences a spectrum of behaviors including motor, learning, reward, motivation and cognition. In accordance with its diverse functions, dopaminergic dysfunction is implicated in a range of disorders affecting millions of people, including Parkinson’s disease (PD), schizophrenia, addiction and depression. How a small group of neurons underpins a gamut of key behaviors and diseases remains enigmatic. We postulated that there must exist several molecularly distinct dopaminergic neuron populations that, in part, can account for the plethora of dopaminergic functions and disorders. We are currently working to test this hypothesis and define dopamine neuron subtypes.
Topic 3. MicroRNAs in Schwann cell (SC) differentiation
MicroRNAs, by modulating gene expression, have been implicated as regulators of various cellular and physiological processes including differentiation, proliferation and cancer. We have studied the role of microRNAs in Schwann cell (SC) differentiation by conditional removal of the microRNA processing enzyme, Dicer1 (Yun et al, 2010, J Neurosci) . We reveal that mice lacking Dicer1 in SC (Dicer1 cKO) display a severe neurological phenotype resembling congenital hypomyelination. SC lacking Dicer1 are stalled in differentiation at the promyelinating state and fail to myelinate axons. We are beginning to determine the molecular basis of this phenotype. Understanding this will be important not only for congenital hypomyelination, but also for peripheral nerve regeneration and SC cancers.
For more information, please see Dr. Awatramani's faculty profile.
View Dr. Awatramani's complete list of publications in PubMed.
Rajeshwar Awatramani, PhD at 312-503-0690
Based at Cognitive Neurology and Alzheimer Disease Center, our laboratory uses multimodal neuroimaging, especially functional magnetic resonance imaging (fMRI), to study the underlying neural mechanisms of language impairment (aphasia) and impairment in other areas of cognition.
For more information about the Bonakdarpour Lab, please visit the Bonakdarpour Laboratory website.
Studies the role of Ca2+ signaling in synucleinopathies using diverse model systems from yeast to human neurons.
We are focused on a group of neurodegenerative diseases collectively known as synucleinopathies, characterized by the aggregation of α-synuclein (α-syn). These include Parkinson's Disease, Dementia with Lewy bodies and Multiple Systems Atrophy among others. We use diverse systems that span from yeast to mammalian models to study these diseases. In particular, we are interested in the role Ca2+ signaling plays in the toxicity caused by α-syn and to delineate basic mechanisms of Ca2+ signaling relevant to neuronal physiology.
Please see Dr. Caraveo Piso's publications on PubMed.
Assistant Professor in Neurology
Genetic causes and pathogenic mechanism that underlie epilepsy
The primary goal of our research is to use gene discovery and molecular biology approaches to identify new treatments for epilepsy. We aim to 1) identify the genetic causes of epilepsy, 2) use stem cell models to understand how genetic mutations can cause epilepsy, 3) develop and test new therapeutics for this condition. Our work is based on the promise of precision medicine where knowledge of an individual’s genetic makeup shapes a personalized approach to care and management of epilepsy.
- Next generation sequencing in patients with epilepsy
- Alternative exon usage during neuronal development
- Identify the regulatory elements that control expression of known epilepsy genes
- Stem cell genetic models for studying the epigenetic basis of epilepsy
Please see Dr. Caraveo Piso's publications on PubMed.
Cancer stem cell biology, cellular signaling and therapy responses in human brain tumors, in particular, glioblastoma (GBM)
Integrated genomic analysis by TCGA revealed tat GBMs can be classified into four clinically relevant subtypes, proneural (PN), neural, mesenchymal (Mes) and classical GBMs with each characterized by distinct gene expression signatures and genetic alterations. We reported that PN and Mes glioma stem cells (GSCs) subtypes also have distinct dysregulated signaling pathways. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, invasion/metastasis, angiogenesis and therapy responses of GSCs and GBMs.
1. MicroRNAs (miRs) and non-coding RNAs in GSCs and GBMs – miRs and other small non-coding RNAs act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms. Dysregulated miRs/noncoding RNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of miRs influence GBM malignant phenotypes through interaction with signaling pathways, that in turn, influence proneural (PN)- and mesenchymal (Mes)-associated gene expression in GSCs and GBM phenotypes. We study the molecular consequences and explore clinical applications of modulating miRs and signaling pathways in GBMs. We are establishing profiles of non-coding RNAs in these GSCs and study mechanisms and biological influences of these non-coding RNAs in regulating GSC biology and GBM phenotypes. In addition, we explore novel therapeutic approaches of delivery of tumor suppressive miRs into GSC brain xenografts in animals.
2. Autophagy in GBMs. (Macro)autophagy is an evolutionally conserved dynamic process whereby cells catabolize damaged proteins and organelles in a lysosome-dependent manner. Autophagy principally serves as an adaptive role to protect cells and tissues, including those associated with cancer. Autophagy in response to multiple stresses including therapeutic treatments such as radiation and chemotherapies provides a mechanism for tumor cell to survive and acquire resistance to therapies. Tumors can use autophagy to support and sustain their proliferation, survival, metabolism, invasiveness, metastasis and resistance to therapy. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy proteins regulate GSC and GBM phenotypes and autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We investigate whether disruption of these post-translational processes on autophagy proteins inhibits autophagy and enhances the efficacy of combination therapies for GBMs. We examine whether cross-talks between miRs, autophagy and oncogenic signaling pathways regulate GSC stemness and phenotypes.
3. Heterogeneity, epigenetic regulation, DNA damage and metabolic pathways in GSCs and GBMs. Intratumoral heterogeneity is a characteristic of GBMs and most of cancers. Phenotypic and functional heterogeneity arise among GBM cells within the same tumor as a consequence of genetic change, environmental differences and reversible changes in cell properties. Subtype mosaicism within the same tumor and spontaneous conversion of human PN to Mes tumors have been observed in clinical GBMs. We explore an emerging epigenetic marker with distinct functions such as DNA methylation together with genetic mapping of these markers to assess their contributions to GBM heterogeneity. In addition, compared with PN GSCs, DNA damage and glycolytic pathways are aberrant active in Mes GSCs. We investigate the mechanisms by which these pathways regulate GSC and GBM phenotypes and responses to therapies.
4. Oncogenic receptor tyrosine kinase (RTKs) signaling, small Rho GTPase regulators in GBM and GSCs: Small Rho GTPases such as Rac1 and Cdc42 modulate cancer cell migration, invasion, growth and survival. Recently, we described mechanisms by which EGFR and its mutant EGFRvIII and PDGFR alpha promote glioma growth and invasion by distinct mechanisms involving phosphorylation of Dock180, a Rac-specific guanidine nucleotide exchange factor (GEF) and DCBLD2, an orphan membrane receptor. We are currently investigating involvement of other modulators/GEFs and other Rho GTPases in modulating GSC and GBM phenotypes and responses to therapy.
View Dr. Cheng's complete list of publications in PubMed.
Shi-Yuan Cheng, PhD at 312-503-5314
Visit us on campus in the Lurie Building, Room 6-119, 303 E Superior Street, Chicago, Illinois 60611.
Our research focuses on the neural and computational principles of reward-guided behavior.
We study brain systems involved in learning, generalization and decision-making such as the striatum and the orbitofrontal cortex. For this, we use a combination of human psychophysics, computational models, fMRI and advanced multivariate analyses techniques borrowed from machine learning. This research may pave the way for understanding decision-making deficits in neurological diseases and should ultimately lead to novel diagnostic markers and treatment strategies for these disorders.
Thorsten Kahnt, PhD at 312-503-2896
Focusing on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system.
The Kessler laboratory focuses on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system. A major interest of the laboratory has been the role of bone morphogenetic protein (BMP) signaling in both neurogenesis and gliogenesis and in regulating cell numbers in the developing nervous system. Both multipotent neural stem cells and pluripotent embryonic stem cells are studied in the laboratory. Recent efforts have emphasized studies of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hIPSC). The Kessler lab oversees the Northwestern University ESC and IPSC core and multiple collaborators use the facility. In addition to the studies of the basic biology of stem cells, the laboratory seeks to develop techniques for promoting neural repair in animal models of spinal cord injury and stroke. In particular, the lab is examining how stem cells and self-assembling peptide amphiphiles can be used together to accomplish neural repair. The lab is also using hIPSCs to model Alzheimer’s disease and other disorders.
For more information see the faculty profile of John A Kessler, MD.
View Dr. Kessler's full list of publications in PubMed.
Our laboratory investigates the molecular mechanisms that give rise to neurological diseases using human stem cell-derived neuronal subtypes.
The broad objective of our laboratory is to understand the nature of the degenerative processes that drive neurological disease in human patients. We are primarily interested in Amyotrophic Lateral Sclerosis (ALS), Epileptic Syndromes as well as the age-associated changes that take place in the Central Nervous System (CNS). We pursue this objective by creating in vitro models of disease. We utilize patient-specific induced pluripotent stem cells and direct reprogramming methods to generate different neuronal subtypes of the human CNS. We then study these cells by a combination of genomic approaches and functional physiological assays. Our hope is that these disease model systems will help us identify points of effective and targeted therapeutic intervention.
View Dr. Kiskinis' publications at PubMed
Evangelos Kiskinis, PhD
Assistant Professor of Neurology
Understanding the mechanisms of neuronal dysfunction in neurodegenerative disorders that affect children and adults.
The overarching goal of my laboratory is to study rare diseases such Huntington’s and genetic forms of Parkinson’s disease, as a window to understanding neurodegeneration across the lifespan. More recently, we have focused on rare lysosomal diseases such as Gaucher’s in order to identify specific targets and mechanisms that contribute to neurodegeneration in Parkinson’s and related synucleinopathies. It is expected that such defined targets will facilitate mechanism-based development of targeted therapies for children with neuronopathis Gaucher’s disease as well as adult-onset synucleinopathies such as Parkinson’s disease. To validate and study these targets and novel therapies in human neurons, we have utilized induced pluripotent stem cells (iPS) generated by reprogramming of patient-specific skin fibroblasts. These iPS cells are differentiated into specific neuronal subtypes in order to characterize the contribution of genetic, epigenetic and environmental factors to disease mechanisms and to test novel therapeutic approaches.
View Dr. Krainc's full list of publications in PubMed.
Dimitri Krainc, MD, PhD
Ward Professor and Chairman
Investigating the genetics of Parkinson’s disease and other neurodegenerative diseases.
The characterization of how genetic changes contribute to increasing disease risk or to disease causality is key to understanding the underlying disease etiology. Through the bioinformatics analysis of next generation sequencing data (whole genome or exome), the Lubbe lab aims to identify novel genes or loci that when altered may contribute to the development of Parkinson’s disease and other neurodegenerative diseases. Furthering our knowledge of the processes that cause Parkinson’s disease could potentially pave the way to the development of novel treatments.
Steven Lubbe, PhD
Investigating cellular self-renewal systems, amyloid formation in the brain, and the relationship of these processes to neurodegeneration and aging.
We are investigating cellular self-renewal mechanisms, amyloid formation in the brain, and the relationship of these processes to neurodegeneration and aging. We primarily use human neurons made from induced pluripotent stem cells as well as in vitro protein aggregation models to delineate the pathogenic mechanisms of age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Our group is largely focused on utilizing neurons from rare lysosomal diseases to study how alterations in biomolecule degradation pathways influence the accumulation and conformation of disease-linked proteins such as alpha-synuclein. Another major effort of the lab is to determine how amyloid formation influences cellular self-renewal mechanisms in neurons, such as lysosomal clearance of damaged macromolecules, and the effect on the aging process.
We use the following techniques and model systems:
- Differentiation of induced pluripotent stem cells into midbrain dopamine neurons to model both rare and common neurodegenerative diseases.
- Analytic biochemical techniques, such as HPLC and size exclusion chromatography, to study protein accumulation and misfolding in neurons.
- Analysis of protein and lipid degradation pathways in neurons with a focus on the autophagic-lysosomal clearance system by a variety of biochemical and cell biological techniques
- Primary neuronal cultures and transgenic mice to study the effect of metabolic pathways on protein accumulation and aging.
- Recombinant protein purification of disease-related proteins to study conformational changes in cell-free in vitro systems.
Joe Mazzulli, PhD at 312-503-3933
Our laboratory investigates the molecular and physiological mechanisms underlying neuropathic pain in hereditary and acquired peripheral neuropathies with particular focus on Painful Diabetic Neuropathy (PDN).
PDN is a debilitating affliction present in 26% of diabetic patients with substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the molecular and electrophysiological mechanisms underlying neuropathic pain in diabetes are not well understood.
Neuropathic pain is caused by sustained excitability in sensory neurons which reduces the pain threshold, so that pain is produced in the absence of appropriate stimuli. Towards designing more effective therapeutics, our goal is to identify the molecular and physiological mechanisms that shape sustained excitability in sensory neurons responsible for the transition to neuropathic pain in peripheral neuropathies. More specifically we are investigating the role of molecules involved in inflammation such as chemokine and the potential role of microRNAs.
We take advantage of an integrated approach combining pain behavioral tests, electrophysiology studies including current clamp recordings, in vitro and in vivo calcium imaging studies, confocal studies with conditional and transgenic mouse genetic and chemo-genetic silencing of sensory neuron subtypes using mutated hM4D receptor (DREADD) receptors.
For more publication information see PubMed and for more information see the faculty profile of Daniela Maria Menichella, MD/PhD.
Daniela Maria Menichella, MD, PhD, at 312-503-3223
Investigating Alzheimer's disease and related disorders.
As the director of the NIH-funded Cognitive Neurology and Alzheimer’s Disease Center (CNADC), Dr. Mesulam’s research focuses on cognition and aging. The CNADC’s research ranges from evaluating quality-of-life interventions for Alzheimer’s disease, to understanding the underlying molecular mechanisms of neurodegenerative diseases, and everything in between. Many of the research studies at the CNADC are related to primary progressive aphasia (PPA), a rare dementia syndrome characterized by the progressive loss of language abilities with relative sparing of other areas of cognition. As one of the top referral centers for PPA in the world, they maintain a large cohort of patients who are thoroughly studied using a variety of techniques, including MRI, ERP, and neuropsychological testing. All research patients have the opportunity to participate in the Brain Donation Program, which allows researchers to understand the link between clinical presentation and underlying neuropathologic disease.
For more information please see the faculty profile of M Marsel Mesulam, MD or visit the The Cognitive Neurology and Alzheimer’s Disease Center (CNADC) website.
Clinical and translational research to devise new treatments, improve protocols, and maximize quality of life for patients with acute neurological injuries.
The section of neurocritical care combines researchers working on complementary areas of neurological emergencies. Ongoing projects include cerebrovascular autoregulation and cognition (Farzaneh Sorond, MD, PhD), patient-centered outcomes research, translational research for acute intracerebral hemorrhage such as acute correction of platelet activity (Andrew Naidech, MD, MSPH), sleep dysfunction and circadian rhythms in acute illness (Matthew Maas, MD), cerebral edema and hepatic encephalopathy (Eric Liotta, MD), and basic neuroscience (Minjee Kim, MD).
Professor of Neurology
Seeking to understand the cellular basis of neurodegeneration.
The long-term goal of my laboratory is to understand the cellular basis of neurodegeneration. We are testing the idea that neurodegeneration results from derangements in relatively few but strategic sub-cellular pathways. By identifying critical components of these pathways one could begin to not only understand the biology of neurodegeneration, but also embark on the design of novel therapeutic agents.
We are currently studying the autosomal dominant disorder Spinocerebellar Ataxia Type 1 (SCA1), a relentless disease that affects cerebellar Purkinje cells and brainstem neurons. This disorder is caused by a polyglutamine expansion in the involved disease protein and is thus similar to a growing number of disorders, including Huntington disease, that share this mutational mechanism. Patients with SCA1 begin to display cerebellar signs characterized by motor incoordination or ataxia in early to mid adulthood. Unfortunately there is no treatment for this disease and patients eventually succumb from the complications of brainstem dysfunction.
Testing the transcriptional hypothesis in SCA1 pathogenesis:
One of the earliest features of this disease is change in the gene expression signature within neurons affected in this disease. We are elucidating the pattern of gene expression changes in the vulnerable Purkinje cell population and identifying the contribution of these alterations to pathology.
Testing the role of the vascular and angiogenic factor VEGF in SCA1 pathogenesis.
One of the genes that we have already found to be down-regulated is the neurotrophic and angiogenic factor VEGF. Importantly, we have discovered that genetic or pharmacologic replenishment of VEGF mitigates SCA1 pathogenesis. These results suggest a novel therapeutic strategy for this incurable disease and a possible cross-talk between the degenerating cerebellum and its microvasculature. We are pursuing mechanistic experiments to learn how low VEGF mediates SCA1 pathology. In addition, we are working actively towards testing the potential for VEGF as a therapy in human ataxic disorders.
Testing the role of ataxin-1 misfolding and clearance in disease pathogenesis.
Several studies suggest that ataxin-1 accumulates in neurons because of its inability to be cleared by the protein-misfolding chaperone pathway. We are testing different strategies to promote ataxin-1 clearance.
In addition to spinocerebellar ataxia, we are also studying genetic parkinsonian and dystonic syndromes.
View Dr. Opal's full list of publications at PubMed
Puneet Opal, MD, PhD, at 312-503-4699
Understanding the cortical component of motor neuron circuitry degeneration in ALS and other related disorders.
The Les Turner ALS Laboratory II at Northwestern
We are interested in the cellular and molecular mechanisms that are responsible for selective neuronal vulnerability and degeneration in motor neuron diseases. Our laboratory especially focuses on the corticospinal motor neurons (CSMN) which are unique in their ability to collect, integrate, translate and transmit cerebral cortex's input toward spinal cord targets. Their degeneration leads to numerous motor neuron diseases, including amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis.
Investigation of CSMN require their visualization and cellular analysis. We therefore, generated reporter lines in which upper motor neurons are intrinsically labeled with eGFP expression. We also characterized progressive CSMN degeneration in various mouse models of motor neuron diseases and continue to generate reporter lines of disease models, in which the upper motor neurons express eGFP.
The overall goal in our investigation, is to develop effective treatment strategies for ALS and other related motor neuron diseases. We appreciate the complexity of the disease and try to focus the problem from three different angles. In one set of studies, we try to reveal the intrinsic factors that could contribute to CSMN vulnerability by investigating the expression profile of more than 40,000 genes and their splice variations at different stages of the disease. In another set of studies, we try to understand the role of non-neuronal cells on motor neuron vulnerability and degeneration, using a triple transgenic mouse model, in which the cells that initiate innate immunity are genetically labeled with fluorescence in an ALS mouse model. These studies will not only reveal the genes that show alternative splice variations, but also inform us on the canonical pathway and networks that are altered with respect to disease initiation and progression.
Even though the above mentioned studies, which use pure populations of neurons and cells isolated by FACS mediated approaches, will reveal the potential mechanisms that are important for CSMN vulnerability, it is important to develop therapeutic interventions. One of the approach we develop is the AAV-mediated gene delivery directly into the CSMN via retrograde transduction. Currently, we are trying to improve CSMN transduction upon direct cortex injection.
Identification of compounds that support CSMN survival is an important component of pre-clinical testing. We develop both in vitro and in vivo compound screening and verification platforms that inform us on the efficiency of compounds for the improvement of CSMN survival.
In summary, we generate new tools and reagents to study the biology of CSMN and to investigate both the intrinsic and extrinsic factors that contribute to their vulnerability and progressive degeneration. We develop compound screening and verification platforms to test their potency on CSMN and develop AAV-mediated gene delivery approaches. Our research will help understand the cellular basis of CSMN degeneration and will help develop novel therapeutic approaches.
View Dr. Ozdinler's full list of publications at PubMed
Hande Ozdinler, PhD at 312-503-2774
The Stroke Research Program aims to develop novel biomarkers and treatments, improve access to and delivery of proven stroke treatments, and reduce disability and death from the disease.
Stroke and related cerebrovascular conditions affect approximately nearly 1,000,000 patients each year in the United States and is the 5th leading cause of death. Though mortality has declined with improved acute treatment and stroke centers of excellence, disability from stroke remains a major health care problem with annual costs exceeding $70 billion per year and expected to rise with an aging population in the coming decades.
The research program focuses on 3 areas: 1) imaging markers of stroke risk; 2) health services delivery, population health, and quality of life; and 3) novel treatments for stroke. Our group has worked on novel imaging tools for the evaluation of cerebral blood flow using MRI, CT, and Transcranial Doppler. These tools will allow us to apply personalized or precision medicine using imaging biomarkers to understand the individual patient cerebrovascular biology and target novel therapies. We also partner with the Institute of Public Health and Medicine (IPHAM) and its Centers of Healthcare Studies, Patient-Centered Outcomes, and Community Health to study novel approaches to system-based and community-based barriers to access to high standard stroke care and treatments. As the NIH-funded StrokeNet’s Regional Coordinator Center for Chicago, we also are actively involved in novel treatment trials that bring cutting-edge medications and devices to our stroke patients.
Research in the Savas lab is aimed at accelerating our understanding of the proteins and proteomes responsible for neurodevelopmental and neurodegenerative diseases.
We use biochemistry with discovery-based mass spectrometry to identify the protein perturbations which drive synaptopathies and proteinopathies. Groups of perturbed proteins serve as pathway beacons which we subsequently characterizes in hopes of finding new pathogenic mechanisms and potential future therapeutic targets.
Please see Dr. Savas' publications on PubMed.
Jeffrey N Savas, PhD
Assistant Professor in Neurology
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
Investigating ways to assist people with neurologic disorders through brain-machine interfaces.
The goal of our research is to help people with neurologic disorders, especially those who are severely paralyzed from stroke, spinal cord injury, cerebral palsy, or ALS. Our research centers around using neural prosthetics, i.e., human machine interfaces, to help restore or replace function of the injured nervous system. We study brain-machine interfaces in monkeys and humans, allowing them to control a computer cursor or virtual hand directly from their brain signals. These signals are obtained via electrodes implanted in or on the surface of the brain or dura mater. In addition, we are investigating the potential to decode a person’s intended speech directly from his or her brain and using this to restore communication to people who have lost it due to severe paralysis. We also use this powerful paradigm to study the underlying relationship between different types of brain signals, for example, the relationship between field potentials (summed from many neurons in the network) and action potentials of individual neurons. Finally, we are developing a myoelectric computer interface to help survivors of stroke regain function in their arms.
Marc W Slutzky, MD, PhD, at 312-503-4653
Understanding neurovascular mechanisms responsible for acute and chronic brain injury.
Our research program is directed at understanding neurovascular function in health and disease. Specifically, we have been studying the association between cerebral blood flow regulation, structural changes in the brain and the clinical outcomes of acute and chronic cerebrovascular injury. In acute neurovascular disorders, we have validated several novel indices of cerebral blood flow regulation which can now be used to predict the development of vasospasm in subarachnoid hemorrhage and hematoma expansion in patients with intraparenchymal hemorrhage. The availability of these early non-invasive biomarkers will have a significant impact on early interventions to improve outcome in patients with subarachnoid and intraparenchymal hemorrhage. Similarly, in chronic neurovascular disorders associated with aging and neurodegenration, we have been examining the contribution of vascular disease to mobility impairment and cognitive decline. We have shown that our non-invasive biomarkers of vascular function are strongly associated with cerebral small vessel disease as well as motor and cognitive impairment. Our goal is to expand these studies to include other neurological disorders such as stroke, pre-eclampsia, traumatic brain injury and dementia. Having non-invasive, real-time measure of neurovascular function which can predict clinical outcome in the early phases of brain injury will have significant implications on clinical trials and therapeutic targets designed for the treatment and prevention of these various acute and chronic neurovascular injuries.
View Dr. Sorond's full list of publications at Pubmed.
Defining and targeting the oncogenome of Glioblastoma.
Our research program is aimed at understanding the genetic program that underlies the pathogenesis of Glioblastoma multiforme (GBM), the most prevalent and malignant form of brain cancer. Applying a combination of cell/molecular biology, oncogenomic and mouse engineering approaches, we are dedicated to systematically characterize novel gliomagenic oncogenes and tumor suppressors. We will functionally delineate and validate these pathways using cell culture and animal models and develop novel nanotechnological approaches to target these aberrations in established tumors.
View Dr. Stegh's full list of publications at PubMed
Alexander Stegh, MD, PhD, at 312-503-2879
The Wu Laboratory seeks to understand molecular mechanisms regulating gene expression and their involvement in the pathogenesis of age-related diseases, including neurodegeneration and tumor metastasis.
RNA Processing and Neurodegeneration
Accumulating evidence supports that aberrant RNA processing represents a general pathogenic mechanism for neurodegeneration, including dementia and amyotrophic lateral sclerosis (ALS). A number of RNA binding proteins (RBPs) have been associated with neurodegenerative diseases, especially various proteinopathies. Recent studies have defined TDP-43 and FUS proteinopathies, a group of heterogeneous neurodegenerative disorders overlapping with dementia, including frontotemporal lobar degeneration (FTLD) and ALS. Several important questions drive our research: what is physiological function of these RBPs? What are the fundamental mechanisms by which genetic mutations in or aberrant regulation of these RBPs cause neural damage? What are the earliest detectable molecular and cellular events that reflect the neural damage in these devastating neurological diseases? How to reverse/repair the neural damage and slow down the progression of these devastating diseases.
To address these questions, we have established cellular and animal models for both TDP-43 and FUS proteinopathies (Li et al, 2010;Barmada et al, 2010; Chen et al, 2011; Fushimi et al, 2011). Using combined biochemical, biophysical, molecular biology and cell biology approaches, we have begun to examine the molecular pathogenic mechanisms underlying neurotoxicity induced by TDP-43 and FUS. Our recent work using atomic force microscopy (AFM), electron microscopy (EM) and (NMR) approaches has shown the biochemical, biophysical and structural similarities between TDP-43 and classical amyloid proteins (Guo et al, 2011; Xu et al, 2013; Bigio et al, 2013). Our study has defined a minimal amyloidogenic region at the carboxyl terminal domain of TDP-43 that is sufficient for amyloid fibril formation and neurotoxicity (Guo et al, 2011; Zhu et al, unpublished). Using cellular and animal models for FUS proteinopathy, we have begun to identify the earliest detectable cellular damage caused by mutations in and overexpression of the human FUS gene. Our data have provided new insights into pathogenic mechanisms underlying these proteinopathies and suggested candidate targets for developing therapeutic approaches.
A critical step in mammalian gene expression is the removal of introns by the process of pre-mRNA splicing. Alternative pre-mRNA splicing, the process of generating multiple mRNA transcripts from a single genetic locus by alternative selection of distinct splice sites, is one of most powerful mechanisms for genetic diversity and an excellent means for fine-tuning gene activity. Many genes critical for neuronal survival and function undergo extensive alternative splicing. Splicing defects play important roles in neurodegenerative disorders such as dementia and motor neuron diseases. For example, splicing mutations in the human tau gene and imbalance of tau splicing isoforms lead to frontotemporal lobar degeneration with tau-positive pathology (FTLD-tau). To understand mechanisms underlying FTLD-tau, we have set up a model system and developed a number of biochemical, molecular and cell biological assays to study alternative splicing of the human tau gene. Our work has led to the identification of a number of cis-elements and trans-acting RBPs controlling tau alternative splicing (Kar et al, 2006; Wu et al, 2006; Kar et al, 2011; Ray et al, 2011). Our experiments have begun to reveal previously unknown players in FTLD-tau and provided new candidate target genes for developing therapeutic strategy (Donahue et al, 2006; unpublished).
Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis
Another line of our research focuses on the cellular and molecular mechanisms regulating cell migration and cancer metastasis. Previous studies from our group and others led to the discovery of Slit as a prototype of neuronal guidance cue. Our studies have shown that Slit interacts with Roundabout (Robo) and acts as a chemorepellent for axons and migrating neurons (Wu et al, 1999; Li et al, 1999;Yuasa-Kawada et al, 2009). Our work has demonstrated that Slit-Robo signaling modulates chemokines and inhibits migration of different types of cells, including cancer cells. The observation that Slit is frequently inactivated in a range of tumors suggests an important role of Slit in tumor suppression. We have established several assays and shown that Slit inhibits invasion and migration of cancer cells, including breast cancer, glioma and prostate cancer. We are using combined molecular and cell biology approaches to dissecting Slit-Robo signaling in neuronal guidance and tumor suppression. Our research has provided new insights into signal transduction pathways mediating Slit function. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis will likely provide novel approaches to cancer metastasis.
View a full list of publications by Jane Wu at PubMed
Jane Wu, MD, PhD, at 312-503-0684
Basic, translational and clinical research linking circadian rhythms and sleep to health outcomes and developing innovative treatments for sleep and circadian disorders.
The Sleep and Circadian Rhythms Research Program has a large research portfolio and a history of successful NIH funding of cutting-edge translational research and clinical trials in the area of sleep and circadian medicine. Research projects include basic studies on mechanisms of sleep and circadian rhythms regulation as well as translational and patient oriented studies on the role of sleep and circadian rhythms on neurocognitive function, cardio-metabolic health, neurodegeneration and other neurological disorders. The program also has extensive history collaborating with institutions throughout the country on large-multi site, multi-year studies and trials.
Currently, faculty are Principal Investigators or collaborators on studies to understand the mechanisms linking sleep quality, circadian alignment with neurocognitive impairment, mood, cardiovascular and metabolic risk in populations at risk for sleep and circadian disorders.
Phyllis C Zee, MD, PhD at 312-503-4409.
We use fMRI, EEG and invasive EEG methods to study neural oscillations in the human olfactory system, their link to the respiratory cycle, and their propagation to downstream limbic areas involved in emotion and memory processing.
The respiratory rhythm is inherently linked to olfaction; it is not possible to encounter an odor without first inhaling through the nose. Thus respiration imposes a natural rhythm of stimulus sampling in the olfactory system. In the mammalian olfactory bulb, local field potentials oscillate in phase with breathing, regulating cortical excitability, synchronizing activity within cell assemblies and coordinating network interactions, thus shaping olfactory sensory coding, memory and behavior. Due to timing constraints with neuroimaging techniques such as functional magnetic resonance imaging (fMRI), and anatomical constraints with surface EEG recordings, very little is known about respiratory oscillations in the human olfactory system. We use invasive EEG methods (iEEG) to examine how the respiratory rhythm is represented in the human olfactory system, and how this representation changes during different attentional states, and in the presence of odor. We are also interested in the propagation of respiratory oscillations from olfactory cortex to other nearby limbic areas such as the amygdala and the hippocampus, and how these limbic respiratory-linked oscillations impact cognitive functions. We are currently developing fMRI and surface EEG protocols for studying human respiratory oscillations originating in olfactory brain regions that don’t require iEEG methods.
Another goal of the lab is to understand the neural correlates of olfactory attentional mechanisms. The olfactory system is anatomically unique in that it has no pre-cortical thalamic relay. Rather, the olfactory system has a very small contingent of fibers projecting to the mediodorsal thalamic downstream from primary olfactory cortex. While this small contingent likely plays a role in olfactory attention, the unique anatomical organization of the olfactory thalamic relay suggests that olfactory attentional mechanisms may differ from other modalities. We use psychophysics, fMRI and iEEG methods to examine attentional mechanisms such as selective attention and predictive coding within the olfactory system.
Christina M Zelano, PhD
Assistant Professor in Neurology