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Protein Structure and Design

Research into the structural bases of biological function.

Labs in This Area

 Kelly Bachta Lab

Antimicrobial resistance mechanisms and pathogenesis of clinically-important bacterial pathogens including Pseudomonas aeruginosa and Enterococcus faecium

Research Description

 The Bachta laboratory has two main research foci:
  1. We investigate the pathogenesis of Pseudomonas aeruginosa infections using imaging and sequencing techniques to define infection dynamics during the context of infection. P. aeruginosa is a gram-negative bacterium that commonly infects immunocompromised hosts.  Recently, observations revealed that P. aeruginosa traffics to the gallbladder where it rapidly replicates.  Current projects seek to uncover novel genetic elements required for replication in the gallbladder and understand the role that this organ plays in disease outcome and bacterial transmission.
  2. We investigate the development of multidrug resistance phenotypes in clinically relevant pathogens including Pseudomonas aeruginosa and Enterococcus faecium.  We are currently exploring novel pathways involved in colistin resistance in P. aeruginosa and characterizing novel mutations in beta-lactamases that lead to antimicrobial resistance.  Finally, we’ve begun a collaboration with the NMH clinical microbiology laboratory to apply whole-genome sequencing and molecular epidemiology to track outbreaks of vancomycin-resistant Enterococcus in the hospital. 

Overall, our studies utilize a broad range of techniques including animal modeling, molecular and biochemical techniques, bacterial whole genome sequencing and antimicrobial resistance testing to explore bacterial pathogenesis and antimicrobial resistance.  We hope that these basic insights will lead to improved diagnostics and therapeutics for bacterial diseases.  

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

Publications

View Dr. Bachta's complete list of publications in PubMed.

Contact Us

Kelly Bachta, MD, PhD at 312-503-3354

 

 G.R. Scott Budinger Lab

Mechanisms of aging and proteostasis stress

Research Description

The Budinger lab studies the mechanisms underlying the loss of organismal resilience during aging, focusing on the hypothesis that some of these changes are induced by chronic stress to the proteostasis network.  We are particularly interested in how proteostasis stress during aging induces dysfunction in tissue resident macrophages in the lung, brain and skeletal muscle that are important for organ repair.  We use pneumonia as a model of systemic organismal stress in animals that mimics many of the features we see in patients hospitalized for pneumonia in our hospital.

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

Publications

See Dr. Budinger's publications on PubMed.

Contact

Contact Dr. Budinger or the administrative office at 312-908-7737.

 

 Xiaolin He Lab

Mechanisms of signal transmission across the membrane via the cell-surface receptors

Research Description

This laboratory is interested in cancer, neural development and reproduction-related structural mechanisms of how extracellular signals (e.g., growth factors, adhesion molecules and morphogens) are translated into intracellular signals by plasma membrane receptors. We use biophysical methods (crystallography, calorimetry, surface plasmon resonance, analytical ultracentrifugation, etc.) in combination with functional studies to define the physiological states and binding processes of these receptors and their complexes with ligands. Our research targets include receptor tyrosine kinases, Semaphorin and its receptors and leucine-rich-repeat-containing G-protein coupled-receptors.

For more information, visit the faculty profile of Xiaolin He, PhD.

Publications

See Dr. He's publications in PubMed.

Staff Listing

Research Associate:
Xiaoyan Chen

Graduate Student:
Po-Han Chen

Contact Us

Contact Dr. He at 312-503-8030 or the He Lab at 312-503-8029.

 Neil Kelleher Lab

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.

Research Description

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 toward 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 scientist 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.


Publications

View lab publications via PubMed.

For more information, visit the Kelleher Lab Web Page or see Dr. Kelleher's faculty profile.

Contact Us

Contact the Kelleher Lab at 847-467-1086 or 847-467-4362

 Liming Li Lab

Structural properties of prion proteins using yeast as a model organism

Research Description

Prion diseases belong to a class of fatal, infectious neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs), including the bovine spongiform encephalopathies (BSE or mad cow disease) in cattle and Creutzfeldt-Jakob disease (CJD) in human. It is generally accepted that the infectious agent of prion disease is a normal host protein (PrPC) that has adopted a pathogenic conformation that is infectious (PrPSc). Remarkably, there are several atypical yeast proteins capable of existing in multiple stable conformations, each of which is associated with distinct phenotypes. Intriguingly, some of the conformations are able to self-propagate and are “infectious.” They are thus referred to as yeast prions. Our laboratory is interested in study this fascinating prion phenomenon using yeast as a model organism. Yeast offers a powerful system that is amenable to biochemical, cell biological and genetic manipulations. We want to obtain information on the structural properties of yeast prions, their mutual interactions and their interactions with other cellular factors, particularly, with molecular chaperones. We have recently discovered that the yeast heat-shock transcription factor (HSF), a master regulator of molecular chaperones’ production, plays an important role in governing the de novo formation and “strain” determination of yeast prion [PSI+]. We are working toward to identify novel cellular factors that are HSF targets and important for yeast prion formation and inheritance. The function of HSF is evolutionally conserved from yeast to human. We hope that results from our yeast prion studies will provide valuable information on the complex etiology of the devastating prion diseases.

Our laboratory is also interested in investigating how common the prion phenomenon in biology is. We wish to identify potential prion proteins from yeast and other non-yeast model organisms through a combined approach of bioinformatics and genetic screenings. Our ultimate goal is to uncover the mechanisms governing the prion conformational switch and to understand the biological significance of the protein conformation based prion-like inheritance.

For more information, visit the faculty profile of Liming Li, PhD.

Publications

See Dr. Li's publications in PubMed.

Contact

Email Dr. L

 Richard Longnecker Lab

Epstein-Barr virus (EBV) and herpes simplex virus (HSV) entry, replication and pathogenesis.

Research Description

Research in the Longnecker laboratory focuses on herpes simplex virus (HSV) and Epstein-Barr virus (EBV). These viruses typically cause self-limiting disease within the human population but both can be associated with serious complications. EBV is associated with variety of hematopoietic cancers such as African Burkitt lymphoma, Hodgkin Lymphoma and adult T-cell leukemia. EBV-associated lymphoproliferative disease occurs in individuals with congenital or acquired cellular immune deficiencies. The two notable epithelial diseases associated with EBV infection are nasopharyngeal cancer and oral hairy leukoplakia. Similar to EBV, HSV latent infections are very common in humans. HSV typically does not cause severe disease but is associated with localized mucocutaneous lesions, but in some cases can cause meningitis and encephalitis. The Longnecker laboratory focuses on several aspects of EBV and HSV replication and pathogenesis. First, the molecular basis EBV transformation and how it relates to cancer is being investigated. The laboratory is currently screening selective inhibitors that may be beneficial in EBV-associated cancers such as Hodgkin lymphoma, Burkitt lymphoma and proliferative disorders that occur in HIV/AIDS and transplant patients. Second, the laboratory is investigating herpesvirus latency in the human host and pathogenesis associated with infections in humans. In this regard, the laboratory is developing animal models for EBV and HSV infections. Finally, the laboratory is investigating the function of herpesvirus encoded proteins and the cellular receptors that are important for infection both using in vivo culture models as well as animal models. Ultimately, studies by the Longnecker laboratory may provide insight for the development of novel therapeutics for the treatment of herpesvirus infections in humans and better understanding of the herpesvirus life cycle in the human host

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

Publications

See Dr. Longnecker's publications on PubMed.

Contact

Contact Dr. Longnecker at 312-503-0467 or the lab at 312-503-0468 or 312-503-9783.

Lab Staff

Research Faculty

Jia Chen, Qing Fan, Kamonwan "Pear" Fish, Masato Ikeda

Adjunct Faculty

Sarah Connolly, Michelle Swanson-Mungerson

Graduate Students

Cooper Hayes, Daniel Giraldo Perez, Seo Jin Park

Technical Staff

Sarah Kopp, Rachel Riccio, Samantha Schaller, Nanette Susmarski

 Puneet Opal Lab

Seeking to understand the cellular basis of neurodegeneration.

Research Description

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.

Current Projects

  1. 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.

  2. 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.

  3. 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.

For more information see the faculty profile of Puneet Opal, MD, PhD or visit the Opal Lab website.

Publications

View Dr. Opal's full list of publications at PubMed

Contact

Puneet Opal, MD, PhD, at 312-503-4699

Lab Staff

Research Associates

Jessica Huang

Postdoctoral Fellows

Edamakanti Chandrakanth Reddy (Chandu), PhD
Dilyan Dryanovski, PhD
Yuan-shih (Jennifer) Hu, PhD
Eitan Israeli, PhD

Graduate Students

Natalie Frederick
Kevin Murnan

Technical Staff

Vicky Hwang

Undergraduate Student

Sean Bald
In-Won Chang

 Murali Prakriya Lab

Calcium signaling, inflammation, and brain function

Research Description

Research in the laboratory of Murali Prakriya, PhD, is focused on the molecular and cellular mechanisms of intracellular calcium (Ca2+) signaling. Ca2+  is one of the most ubiquitous intracellular signaling messengers, mediating many essential functions including gene expression, chemotaxis and neurotransmitter release. Cellular Ca2+ signals generally arise from the opening of Ca2+-permeable ion channels, a diverse family of membrane proteins. We are studying Ca2+ signals arising from the opening of store-operated Ca2+  channels (SOCs). SOCs are found in the plasma membranes of virtually all mammalian cells and are activated through a decrease in the calcium concentration ([Ca2+]) in the endoplasmic reticulum (ER), a vast membranous network within the cell that serves as a reservoir for stored calcium. SOC activity is stimulated by a variety of signals such as hormones, neurotransmitters and growth factors whose binding to receptors generates IP3 to cause ER Ca2+ store depletion.

The best-studied SOC is a sub-type known as the Ca2+ release activated Ca2+  (CRAC) channel encoded by the Orai1 protein. CRAC channels are widely expressed in immune cells and generate Ca2+  signals important for gene expression, proliferation and the secretion of inflammatory mediators. Loss of CRAC channel function due to mutations in CRAC channel genes leads to a devastating immunodeficiency syndrome in humans. Our goals are to understand the molecular mechanisms of CRAC channel activation, and their physiological roles especially in the microglia and astrocytes of the brain, and in the airway epithelial cells of the lung.

Recent Findings

Despite the fact that CRAC channels are found in practically all cells, their properties and functions outside the immune system remain largely unexplored. In order to fill this gap, we have begun investigation of CRAC channel properties and their functions in two major organ systems: in the brain and the lung.

  • In the brain, we are studying the role of CRAC channels for dendritic Ca2+ signaling in excitatory neurons of the hippocampus, and their role in synaptic plasticity and cognitive functions. We have found that CRAC channels formed by Orai1 are critical for amplifying glutamate receptor evoked calcium signals in dendritic spines of hippocampal neurons, and this step is essential for driving structural and functional measures of synaptic plasticity and cognitive processes involving learning and memory.
  • In a second project, we are studying the role of CRAC channels in driving neuroinflammation. We have found that CRAC channels formed by Orai1 are essential for the production and release of proinflammatory cytokines and chemokines in microglia and astrocytes.  We are examining the relevance of this pathway for mediating inflammatory and neuropathic pain.
  • A third project is examining the role of CRAC channels for mediating pro- and anti-inflammatory processes in the lung. We have found that CRAC channels are a major mechanism for mobilizing Ca2+ signals in lung epithelial cells, and the downstream production of both pro- and anti-inflammatory mediators. We are examining the relevance of this signaling for lung inflammation in the context of asthma.

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

Publications

See Dr. Prakriya's publications on PubMed.

Contact

Contact Dr. Prakriya at 312-503-7030.

Lab Staff

Research Faculty

Megumi Yamashita

Postdoctoral Fellows

Kirill Korshunov, Priscilla Yeung

Graduate Students

Kaitlyn Demeulenaere, Tim Kountz, Michaela Novakovic

Technical Staff

Megan Martin, Martinna Raineri Tapies

 Gabriel Rocklin Lab

We develop high-throughput methods for protein biophysics and protein design, with a focus on protein therapeutics

Research Description

Key questions include: How do protein sequence and structure determine folding stability, conformational dynamics, and resistance to aggregation/degradation-inducing stresses? Can we quantitatively predict these protein "phenotypes" from genotype (sequence) using computational modeling? How do we design protein therapeutics that optimize these phenotypes for a particular application? To answer these questions, we combine large-scale de novo computational protein design with high-throughput methods such as display selections, mass spectrometry proteomics, and next-generation sequencing, enabling us to test thousands of proteins in parallel. By combining these technologies, we seek to develop efficient "design-test-analyze" cycles, iterating our way to an improved, quantitative understanding of protein biophysics and more advanced protein therapeutics.

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

Publications

See Dr. Rocklin's publications on PubMed.

Contact

Contact Dr. Rocklin at 312-503-4892.

Lab Staff

Postdoctoral Fellows

Sugyan Dixit, Jane Thibeault, Kotaro Tsuboyama

Graduate Students

Tae-Eun Kim, Cydney Martell, Claire Phoumyvong

Research Fellows

Radhika Dalal, Andres Lira

Technical Staff

Robert Ludwig

Visiting Scholar

Allan Ferrari

 Karla Satchell Lab

Role of bacterial protein toxins in the pathogenesis of Vibrio vulnificus and Vibrio cholerae

Research Description

My research focuses on the role of secreted protein toxins on bacterial pathogenesis. The toxins we study are members of the MARTX family and are produced by Vibrio cholerae, a pathogen important for the diarrheal disease cholera, and Vibrio vulnificus, a pathogen that causes septicemia and necrotizing fasciitis from seafood consumption as well as wound infections. Our group studies the mechanism of action of these toxins using a combination of cell biology, biochemistry, and structural biology. In addition, we investigate the role of these toxins in pathogenesis using animal and tissue culture models with focus on mechanisms of tissue damage and evasion of innate immune clearance.

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

Publications

See Dr. Satchell's publications on PubMed.

Contact

Contact Dr. Satchell at 312-503-2162 or the lab at 312-503-1503.

Lab Staff

Research Faculty

George Minasov, Ludmilla Shuvalova

Research Project Manager

Nicole Inniss, Lishan Liu

Postdoctoral Fellows

Alfa Herrera, Monica Lemus, Shantanu Shukla

Graduate Students

Caleb Stubbs, Patrick Woida

Technical Staff

Matthew Kieffer, Olga Kiryukhina, Christine Nordloh, Megan Packer, Stephanie Shee, Jacob Vandervaart, Grant Wiersum

Temporary Staff

Carson Bergstrom, Melanie Cruz, Isaac Gershberg, Matthew Lam, Melissa Yuen

 Jeffrey Savas Lab

Research in the Savas lab is aimed at accelerating our understanding of the proteins and proteomes responsible for neurodevelopmental and neurodegenerative diseases.

Research Description

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.

For more information view the faculty profile of Jeffrey Savas, PhD or the Savas Lab website.

Publications

Please see Dr. Savas' publications on PubMed.

Contact Information

Jeffrey N Savas, PhD
Assistant Professor in Neurology
312-503-3089

 

 Hank Seifert Lab

Bacterial pathogenesis, DNA recombination mechanisms, epithelial cell adherence

Research Description

Our laboratory studies the pathogenesis of Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea. This gram-negative bacterium is an obligate human pathogen that has existed within human populations throughout recorded history. We are using a variety of molecular biological, genetic, cell biological and biochemical techniques to investigate the molecular mechanisms controlling gonococcal infection, define mechanisms and pathways of DNA recombination, replication and repair in this human specific pathogen, study the interactions between gonococci and human cells, tissues and the innate immune system and determine how the pilus functions to help mediate genetic transfer and pathogenesis. Our goal is to discover new mechanisms important for the continued existence of this microbe in the human population to further our understanding of how infectious agents have evolved to specifically infect humans.

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

Publications

See Dr. Seifert's publications on PubMed.

Contact

Contact Dr. Seifert at 312-503-9788 or the lab at 312-503-9786.

Lab Staff

Research Faculty

Elizabeth Stohl 

Postdoctoral Fellows

Linda I-Lin Hu, Jayaram Narayana, Ella Rotman

Graduate Students

Wendy Geslewitz

Technical Staff

Hannah Landstrom, Brian Sands, Shaohui Yin 

 Greg Smith Lab

Cell and molecular biology of herpesvirus invasion of the nervous system

Research Description

We investigate the relationship between infection of the nervous system by herpesviruses and disease outcome. Some of the most traumatic diseases – including polio, rabies and encephalitis – result from infections of the nervous system.  In contrast, herpesviruses are highly proficient at infecting the nervous system, yet normally do not cause neurological disease.  This is achieved in part by self-imposed restrictions encoded within the viruses that limit viral reproduction and prevent dissemination into the brain.  For the individual, this results in a relatively benign infection, yet the virus becomes a life-long occupant of the nervous system that will periodically reemerge at body surfaces to infect others. Unfortunately, this infectious cycle can go awry resulting in several forms of severe disease (i.e. keratitis and encephalitis).

We have pioneered methods to genetically manipulate herpesviruses and visualize individual viruses in living neurons. Using these methods, we are studying the mechanisms by which the virus achieves its stringently controlled infectious cycle. Current genetic manipulations are based on a full-length infectious clone of the herpesvirus genome. The clone was made as a bacterial artificial chromosome (BAC) in E. coli. Transfection of purified E. coli BAC plasmid into permissive eukaryotic cells is sufficient to initiate viral infection, allowing for immediate examination of viral mutant phenotypes in a variety of biological assays.  For example, by fusing the green fluorescent protein (GFP) to a structural component of the viral capsid, individual viral particles can be tracked within the axons of living neurons during both entry and egress phases of the infectious cycle. Studies in culture can be complemented by examining the pathogenesis of mutant viruses in rodent models of infection.

Using these methods, we have discovered key aspects of cellular infection, viral assembly and intracellular transport. Looking forward, we are continuing to pursue our multidisciplinary approach of combining neuroscience, cell biology, bacterial genetics and virology to better understand these important pathogens.

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

Publications

See Dr. Smith's publications on PubMed.

Contact

Contact Dr. Smith at 312-503-3745 or the lab at 312-503-3744.

Lab Staff

Research Faculty

Sarah Antinone 

Postdoctoral Fellows

Oana Maier

Graduate Students

Kennen Hutchison, DongHo Kim, Caitlin Pegg, Jen Ai Quan

Technical Staff

John Miller, Austin Stults 

 Dileep Varma Lab

Chromosome segregation, genomic instability and cancer biogenesis

Research Description

The broad area of our research interest is in the cytoskeleton and intracellular motility. The cytoskeletal polymer that we are most interested in is the microtubules and the cytoskeletal process that we are most excited about is the accurate segregation of chromosomes during mitosis. A dividing cell assembles mitotic kinetochores and a mitotic spindle at the onset of mitosis. The kinetochores serve as sites where the microtubules of the mitotic spindle comes in physical contact with the chromosomes and are hence extremely important for accurate chromosome segregation. Improper kinetochore microtubule (kMT) attachments lead to erroneous chromosome segregation, chromosome loss and aneuploidy in turn, which is the leading cause of cancer in tissue cells and of birth defects and miscarriages during human embryonic development.

Over a decade of research had identified the kinetochore-bound Ndc80 complex as the key requirement for the direct physical contact with microtubules of the spindle. But what is still not understood well is how the kinetochores and the Ndc80 complex remains stably attached to the highly dynamic microtubule plus-ends during mitotic metaphase and subsequent chromosome segregation in anaphase. Work is yeast model system had provided us with important insights into the possible mechanism governing this process, but we still do not have a clear mechanistic picture in vertebrate systems. Work in our lab focusses on understanding the molecular mechanisms that are involved the controlling and regulating kinetochore microtubule attachments in vertebrate cells. We are also very interested to delineate the intricate mechanism that link this event with the activation and silencing of the spindle assembly checkpoint which is also absolutely critical for accurate chromosome segregation

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

Publications

See Dr. Varma's publications on PubMed.

Contact

Contact Dr. Varma at 312-503-4318 or the lab at 312-503-0824.

Lab Staff

Postdoctoral Fellows

Shivangi Agarwal, Mohammed Amin, Amit Rahi

Graduate Student

Adriana Landeros

 Martin Watterson Lab

Focusing on the role of protein phosphorylation pathways in disease onset and progression and their potential as drug discovery targets

Research Description

Current Projects

The role of calmodulin (CaM) mediated signal transduction pathways in physiology and pathophysiology

  • Using of emerging technologies to understand how CaM and a CaM-regulated enzyme could be encoded, expressed, regulated and assembled into a calcium signal transduction complex
  • Using of integrative (in vivo) chemical biology and molecular genetics to gain insight into how landmark CaM-regulated protein kinases are involved in physiology and pathophysiology

Integrative chemical biology and development of novel therapeutics for attenuation of disease progression

  • Using the “smart chemistry” approach integrated with “smart biology” screens for rapid discovery of novel small molecules with potential use in targeting pathophysiology progression related to diseases ranging from neurological disorders, cancer, inflammatory conditions, cardiovascular and pulmonary disease
  • Discovering and developing novel small molecule compounds that selectively attenuate the increased production of proteins called proinflammatory cytokines, which can cause tissue injury and disease when produced in excess

We ultimately hope to find, by targeting pathophysiology mechanisms which contribute to disease progression, a series of novel small molecules with potential to be effective against a variety of disorders.

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

Contact

Contact Dr. Watterson at 312-503-0657.

Lab Staff

Adjunct Professor

Jeff Pelletier

Research Faculty

Saktimayee Roy

Senior Research Associate

Tatiana Pundy

 Jane Wu Lab

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.

Research Description

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. 

For more information please view the faculty profile of Jane Wu, MD, PhD or visit the Wu Lab website.

Recent Publications

View a full list of publications by Jane Wu at PubMed

Contact Us

Jane Wu, MD, PhD, at 312-503-0684

 

 Jing Zheng Lab

Hearing and cochlear amplification, deafness-related proteins and cell death

Research Description

The goal of my lab is to identify and investigate molecules that play important roles in mammalian hearing, thus enriching our understanding of cochlear physiology and further developing a better strategy to prevent hearing loss. Deafness is commonly caused by defects in inner ear hair cells. In mammalian cochleae, inner hair cells (IHCs) function as sensory receptors conveying sound-related information to the central nervous system. Outer hair cells (OHCs) amplify the mechanical signals delivered to IHCs. The cooperation between IHCs and OHCs results in sensitive hearing and sharp tuning. Complex and sophisticated protein networks in hair cells facilitate their functions. Very often, genetic defects in a single protein can interfere with the entire network and cause deafness. Our research has been centered on several important proteins expressed in cochlea.

1. Molecular basis of cochlear amplification. OHCs undergo rapid somatic length changes when the voltage across their membrane is altered. This unique somatic electromotility provides the local mechanical amplification of the cochlear response to sound. Without OHCs, hearing threshold is elevated by 40-50 dB and frequency resolution deteriorates. Prestin is the motor protein of OHCs and is required for cochlear amplification (Zheng et al., Nature, 2000). Coincidently, prestin is only expressed in OHCs, which are also the most vulnerable cells in the organ of Corti. In the past, studying OHC amplification mechanisms and preventing OHC loss were considered two separate research fields. However, our recent data indicate a close connection between prestin's function and the vulnerability of OHCs to a variety of ototoxic exposures. To understand this link, we focus on investigating the molecular mechanism of the motor protein prestin using various cellular, biochemical and molecular biological methods.

2. Protein network of hair cells. We are focus on several deafness-related proteins: CDH23, CEACAM16 and Marshalin. Cadherin 23 is a tip-link protein of hair cells. CEACAM16 is an adhesive protein localized at the tectorial membrane (Zheng et al. PNAS, 2011). Marshalin is another newly identified microtubule minus-end binding protein that is expressed in the inner ear. Its expression is developmentally controlled (Zheng et al., Biology Open 2013). Very often, genetic defects in a single protein can interfere with the entire network and cause deafness. We are in the process of investigating interactions among these proteins and their physiological roles for normal hearing and deafness.

For more information, visit the faculty profile of Jing Zheng, PhD.

Publications

View Dr. Zheng's publications in PubMed

Contact

Dr. Zheng

Phone 312-503-3417

Lab Staff

Research Associate

Satoe Humma

Research Technician

Vincent Mui

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