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Lung

Research into the physiologic functions and diseases of the lung.

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.

 

 Lillian Eichner Lab

Transcriptional dependencies in cancer at the intersection of epigenetics, signaling and metabolism

Research Description

The Eichner lab studies transcriptional dependencies in cancer development, progression and resistance mechanisms. We endeavor to elucidate in vivo transcriptional dependencies at the intersection of epigenetics, signaling, and metabolism to reveal and harness therapeutically targetable transcriptional vulnerabilities in cancer.

Project 1

LKB1 (STK11) is among the most frequently mutated genes in Non-Small Cell Lung Cancer (NSCLC), where it is inactivated in about 20 percent of cases. Leveraging immune-competent genetically engineered mouse models to answer key questions in vivo, our work has revealed key insights into the molecular mechanisms driving this disease. We have identified that transcription plays an important and previously underappreciated role in mediating LKB1 function. Future work will continue utilizing mechanistic understanding to explore novel in vivo transcriptional dependencies and therapeutic liabilities of LKB1 mutant tumors.

Project 2

We have identified critical roles of the druggable epigenetic regulator Histone Deacetylase 3 (HDAC3) in lung tumors. We found that HDAC3 directly represses the secretory component of the cellular senescence program, the SASP, and restrains recruitment of T-cells into tumors in vivo. Future work will continue defining the molecular mechanisms mediating HDAC3’s contribution to tumorigenesis, and further explore epigenetic regulation of the senescence program.

For lab information, publications and more, see Dr. Eichner's faculty profile and laboratory website.

Publications

See Dr. Eichner's publications on PubMed.

Contact

Contact Dr. Eichner.

 Cara Gottardi Lab

The Gottardi Lab investigates how cells adhere to each other and how this adhesion is regulated and controls gene expression in heath and disease.

The ability of individual cells to adhere and coalesce into distinct tissues is a major feature of multicellular organisms. Research in my laboratory centers on a protein complex that projects from the cell surface and forms a structural “Velcro” that holds cells to one another. This complex is comprised of a transmembrane “cadherin” component that mediates Ca++-dependent homophilic recognition and a number of associated “catenins” that link cadherins to the underlying cytoskeleton.  A major focus in our lab is to understand how these catenins direct static versus fluid adhesive states at the plasma membrane, as well as gene expression and differentiation in the nucleus. These basic questions are shedding new light on how dysregulation of the cadherin/catenin adhesion system drives pathologies such as asthma, fibrosis and cancer.

Publications

See Dr. Gottardi's publications in PubMed.

For more information, please see Dr. Gottardi's faculty profile.

Lab Staff

Annette Flozak
Research Technologist
312-503-0409

 

 SeungHye Han Lab

Mitochondrial metabolism and lung stem cells in lung injury and repair

Research Description

The Han lab studies how mitochondrial metabolism regulates lung stem/progenitor cells by focusing on the different functions of each mitochondrial electron transport chain complex. We are particularly interested in how lung epithelial cells repair after injury and what factors lead to aberrant repair resulting fibrosis. Mitochondrial dysfunction is commonly observed in patients with severe pneumonia and/or pulmonary fibrosis. Using elaborately designed genetic knock-out and knock-in mouse systems, we are testing whether mitochondrial electron transport chain complexes are necessary for proper lung epithelial stem/progenitor cell differentiation.  We use viral pneumonia as a model of lung injury and repair in animals. Findings from these studies can be directly applied to the patients hospitalized for pneumonia, influenza, and SARS-CoV-2 infection in our hospital.     

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

Publications

See Dr. Han's publications on PubMed

Contact

Dr. Han

 Karen M. Ridge Lab

The Ridge Lab investigates the role of intermediate filaments in lung pathophysiology

The cytoskeletal protein vimentin plays a key role as a scaffold for the formation and activation of intracellular protein complexes. One such complex is the NLRP3 inflammasome, which assembles in response to danger signals such as influenza A virus or ATP released by damaged cells to produce mature IL-1β and IL-18. These inflammatory cytokines can induce lung injury, which can lead to fibrosis. One of our current goals is to pinpoint vimentin’s role in inflammasome assembly and activation.

Vimentin is also involved in all stages of cancer development, from PI3K/AKT and Erk pathway regulation in tumerigenesis, to its defining role in epithelial-to-mesenchymal transition, to metastatic cell invasion and migration, making it an intriguing therapeutic target. Our purpose in examining vimentin’s role in lung cancer is to determine whether its inhibition might be of benefit to patients.

Publications

View our lab’s publications in PubMed.

To learn more, please visit the faculty profile pages of Karen M. Ridge, PhD

Visit the Ridge Lab Website

Contact Us

Email Dr. Ridge
Phone 312-503-1648 or the Ridge Lab at 312-503-0403

Lab Staff

Alexandra Berr
Graduate Student
312-503-0403

Yuan Cheng
Research Technologist 2
312-503-0403

Mark Ciesielski
Research Technologist 1
312-503-0403

Bria Coates, MD
Assistant Professor
312-227-4800

Jennifer Davis
Research Technologist I
312-503-0403

Francisco Gonzalez, MD
Postdoctoral Research Fellow

Grant Hahn, MD
Critical Care Medicine Fellow

Jennifer Yuan-Shih Hu, PhD
Postdoctoral Research Fellow
312-503-4845

Clarissa Masumi Koch, PhD
Postdoctoral Research Fellow
312-503-0403

Dale Shumaker, PhD
Research Assistant Professor
312-503-1918

Margaret Turner
Research Technologist 1
312-503-4845

 Paul Schumacker Lab

Oxygen sensing in embryonic development, tissue responses to hypoxia and tumor angiogenesis.

Research Description

Our lab is interested in the molecular mechanisms of oxygen sensing and the importance of this process for embryonic development, tissue responses to hypoxia and tumor angiogenesis. We are testing the hypothesis that the mitochondria play a central role in detecting cellular oxygenation and signal the onset of hypoxia by releasing reactive oxygen species (ROS). These signals trigger downstream signal transduction pathways responsible for the transcriptional and post-translational responses of the cell. Transcriptional activation of genes by Hypoxia-Inducible Factor-1 confers protection against more severe hypoxia by augmenting the expression of glycolytic enzymes, membrane glucose transporters and other genes that tend to augment tissue oxygen supply by increasing the release of vascular growth factors such as VEGF, erythropoietin and vasoactive molecules that augment local blood flow. Current experiments are aimed at improving our understanding of how oxygen interacts with the mitochondrial electron transport chain to amplify ROS production and clarifying the targets that they act on to stabilize HIF and activate transcription.

In specific tissues, oxygen sensing is essential for normal function, but it can also contribute to disease pathogenesis.  For example, during mammalian development, the lung tissue is hypoxic and blood flow is restricted in the pulmonary circulation in order to prevent escape of oxygen from the pulmonary capillaries to amniotic fluid.  At birth, inflation of the lung with air causes an increase in lung oxygen levels, which triggers relaxation of pulmonary arteries.  In Persistent Pulmonary Hypertension of the Newborn, failure of the pulmonary circulation to dilate results in elevated pulmonary arterial pressures and significant lung gas exchange dysfunction.  We are testing the hypothesis that pulmonary vascular cells sense O2 at the mitochondria and that ROS released from those organelles trigger an increase in cytosolic calcium, which causes smooth muscle cell contraction.  In adult patients with hypoxic lung disease, similar activation of hypoxic vasoconstriction can lead to chronic pulmonary hypertension, which can progress to right heart failure.  A fuller understanding of the mechanisms of oxygen sensing in health and disease may lead to insights into therapeutic inhibition of this response in disease states.

In solid tumors, consumption of oxygen by highly metabolic tumor cells leads to hypoxia and threatens glucose supplies.  Hypoxic tumor cells retain their oxygen sensing capacity and turn on expression of HIF-dependent genes, leading to tumor angiogenesis and increased blood supply, which permits further growth.  We are currently exploring the hypothesis that the mitochondrial oxygen sensor is required for this response using pursuing genetic models.  A better understanding of how tumor cells detect hypoxia could lead to the discovery of therapeutic approaches that would prevent detection of hypoxia and thereby prevent tumor progression.

For more information visit Dr. Schumacker's faculty profile page

Publications

View Dr. Schumacker's publications at PubMed

Contact

Email Dr. Schumacker

Phone 312-503-1476

 Benjamin Singer Lab

Exploring respiratory failure

Research Description

The Singer Lab focuses on determinants of resolution and repair of acute lung inflammation and injury. Our ultimate goal is to unravel the factors controlling resolution and repair and exploit those factors as therapies for acute respiratory distress syndrome (ARDS)—a devastating disorder responsible for the deaths of tens of thousands of people each year.

For more information, visit the Benjamin Singer Lab site or his faculty profile page.

View Dr. Singer's publications on PubMed.

Contact Us

Email Dr. Singer or contact at 312-908-8163.

 Jacob I. Sznajder Lab

The Sznajder Lab investigates the mechanisms of acute lung injury as related to aging, high CO2, low oxygen, lung cancer and influenza infection.

Seasonal influenza infection affects a significant proportion of the population in the US and worldwide and while most patients infected with influenza A virus (IAV) recover without sequelae, in many patients influenza virus infection may cause ARDS. Alveolar epithelial cells (AEC) are targets for IAV and play an important role in mounting the initial host response. The Sznajder Lab hypothesizes that the alveolar epithelium plays an important effector role in protecting the lung from severe injury. Findings indicate that the degradation of PKCζ, which triggers the down-regulation of Na,K-ATPase, by the E3 ligase HOIL-1L decreases AEC death.  HOIL-1L is a member of the Linear Ubiquitination Assembly Complex (LUBAC) and the lab studies whether LUBAC participates in the modulation of the inflammatory intensity in the lung epithelium during IAV infection. Also, they are investigating the mechanisms by which modest inhibition of the Na,K-ATPase,  whether pharmacologic inhibition of the Na,K-ATPase by cardiotonic steroids such as ouabain are protective by inhibiting virus replication.

Studies suggest that signals from the injured lung during IAV infection disrupt skeletal muscle proteostasis and contribute to skeletal muscle dysfunction. The slower recovery of the skeletal muscle function in aged mice during IAV pneumonia is the consequence of diminished proteostatic reserve in cells responsible for regenerating the damaged skeletal muscle.

Hypercapnia (high pCO2) is observed in patients with lung diseases such as chronic obstructive pulmonary disease (COPD), broncho-pulmonary dysplasia and advanced neuromuscular diseases. The lab hypothesizes that hypercapnia promotes the ubiquitin-proteasome mediated muscle degradation and impairs the function of muscle satellite cells required for its regeneration.

Alveolar fluid reabsorption is effected by vectorial Na+ transport via apical Na+ channels and basolateral Na,K-ATPase of the alveolar epithelium. We and others have reported that β-adrenergic agonists upregulate the Na,K-ATPase in AEC  by increasing the traffic and recruitment of Na,K-ATPase containing vesicles into the cell membrane, resulting in increased catalytic activity. Moreover, GPCR-mediated upregulation of the Na,K-ATPase resulted in increased alveolar fluid clearance in normal lungs and in rodent models of lung injury.  We are investigating mechanisms of Na,K-ATPase regulation and active Na+ transport in lungs which will help with the design of new strategies to increase lung edema clearance.

Publications

View Dr. Sznajder's publications on PubMed

For more information visit the faculty profile of Jacob Sznajder, MD.

Contact

Contact Dr. Sznajder at 312-908-7737 or the Sznajder Lab at 312-503-1685.

Lab Staff

Laura Brion, PhD
Visiting Scholar
312-503-1685

Patricia Brazee
DGP Graduate Student
312-503-1685

Ermelinda Ceco, PhD
Postdoctoral Research Fellow
312-503-1685

Nina Censoplano, MD
Fellow, Pediatric Critical Care
312-503-1685

Laura A Dada, PhD
Research Associate Professor
312-503-5397

Jeremy Katzen, MD
Research Fellow
312-503-1685

Emilia Lecuona, PhD
Research Associate Professor
312-503-5397

Natalia Magnani, PhD
Postdoctoral Research Fellow
312-503-1685

Masahiko Shigemura, PhD
Postdoctoral Research Fellow
312-503-1685

Lynn C. Welch
Research Laboratory Manager
312-503-1685

Weronika Zuczek
Research Technologist I
312-503-1685

 Youyang Zhao Lab

The Zhao Lab studies the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury as well as endothelial and smooth muscle cell interaction in the pathogenesis of pulmonary vascular diseases.

Research Description

Recovery of endothelial barrier integrity after vascular injury is vital for endothelial homeostasis and resolution of inflammation. Endothelial dysfunction plays a critical role in the initiation and progression of vascular diseases such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and atherosclerosis. A part of the research in the lab, employing genetically modified mouse models of human diseases, endothelial progenitor cells/stem cells, and translational research approach as well as nanomedicine, is to elucidate the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury and determine how aging and epigenetics regulate these processes (J. Clin. Invest. 2006, 116: 2333; J. Exp. Med. 2010, 207:1675; Circulation 2016, 133: 2447).  We are also studying the role of endothelial cells in regulating macrophage functional polarization and resolving inflammatory lung injury. These studies will identify druggable targets leading to novel therapeutic strategies to activate the intrinsic endothelial regeneration program to restore endothelial barrier integrity and reverse edema formation for the prevention and treatment of ARDS in patients.

Pulmonary hypertension is a progressive disease with poor prognosis and high mortality. We are currently investigating the molecular basis underlying the pathogenesis.  We have recently identified the first mouse model of pulmonary arterial hypertension (PAH) with obliterative vascular remodeling including vascular occlusion and formation of plexiform-like lesions resembling the pathology of clinical PAH (Circulation 2016, 133: 2447). Our previous studies also show the critical role of oxidative/nitrative stress in the pathogenesis of PAH as seen in patients (PNAS 2002, 99:11375; J. Clin. Invest. 2009, 119: 2009). With these unique models and lung tissue and cells from idiopathic PAH patients, we will define the molecular and cellular mechanisms underlying severe vascular remodeling and provide novel therapeutic approaches for this devastating disease. 

The Zhao lab employs the state-of-the art technologies including genetic lineage tracing, genetic depletion, genetic reporter, and CRISPR-mediated in vivo genomic editing as well as patient samples to study the molecular mechanisms of acute lung injury/ARDS, and pulmonary hypertension and identify novel therapeutics for these devastating diseases. Current studies include 1) molecular mechanisms of endothelial regeneration and vascular repair following inflammatory lung injury induced by sepsis and pneumonia; 2) how aging and epigenetics regulate this process; 3) how endothelial cells regulate macrophage and neuptrophil function for resolution of inflammation and host defense; 4) stem/progenitor cells in acute lung injury and pulmonary hypertension and cell-based therapy; 5) mechanisms of obliterative pulmonary vascular remodeling; 6) molecular basis of right heart failure; 7) pathogenic role of oxidative/nitrative stress; 8) lung regeneration; 9) drug discovery; 10) nanomedicine.


Publications

View publications by Youyang Zhao in PubMed.

For more information, visit Dr. Zhao's Faculty Profile page

Contact

Email Dr. Zhao

Contact Dr. Zhao’s Lab at 773-755-6355

Lab Staff

Zhiyu Dai, PhD.
Research Assistant Professor

Xianming Zhang, PhD.
Research Assistant Professor

Narsa Machireddy, PhD.
Research Assistant Professor

Junjie Xing, PhD.
Research Scientist

Colin Evans, PhD.
Research Scientist

Varsha Suresh Kumar, PhD.
Research Scientist

Xiaojia Huang, PhD
Research Scientist

Hua Jin, PhD
Postdoctoral fellow

Yi Peng, PhD
Research Scientist

Mengqi Zhu, M.S.,
Graduate Student

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