CRND Seminar Series

Fall - 2015

 

Fall 2015 CTSS Seminar Guest Lecture

Friday, December 4, 2015

DeBartolo Hall room 208 11 am.

Wyndham Lathem, Ph.D.

Associate Professor, Dept. of Microbiology-Immunology

Northwestern University Feinberg School of Medicine

"How a Single Gene Changed History: Retracing the Evolution of Pneumonic Plague."

Dr. Wyndham Lathem

Seminar on December 4th, 2015

“The adaptation of bacterial pathogens to new hosts and specific microenvironments within the body typically occurs via the combined gain and/or loss of genetic elements during the evolution of the species. Yersinia pestis, responsible for the devastating respiratory infection known as pneumonic plague, is a recently evolved clone of the gastrointestinal pathogen
Y. pseudotuberculosis
, and represents one of the best models to examine the emergence of new virulence traits and mechanisms of disease. In this presentation, I will discuss our recent studies to identify the specific genetic changes that endowed Y. pestis with the ability to infect the lungs as it evolved from Y. pseudotuberculosis over the past 5,00010,000 years. In addition, I will describe how the acquisition of a single gene encoding the outer membrane Pla protease enabled Y. pestis to coopt host fibrinolysis factor plasminogen to cause pneumonic plague, and the surprising role of plasminogen as a “danger signal” to trigger the immune response during infection.”

 

Friday, November 13, 2015

DeBartolo Hall room 319 2:15 pm.

Johan L. Van Hove, M.D., Ph.D.

Professor of Pediatrics, Dept. of Pediatrics

University of Colorado School of Medicine,
Anschutz Medical Campus

"What indicates clinical outcome in nonketotic hyperglycinemia?"

Dr. Johan L. Van Hove

Seminar on November 13th, 2015

“Nonketotic hyperglycinemia is a rare genetic neruometabolic disorder that is caused by deficient activity of the glycine cleavage enzyme. Most children present in the neonatal period with hypotonia, transient apnea, coma and seizures. They go on to develop spasticity, therapy resistant seizures, and complete lack of neurological development. Yet, there are children with this condition, that make substantial developmental progress, have no or easily treatable seizures. In this presentation we will review what distinguishes these different outcomes and how this information can be used for development of treatment.”


 

Friday, November 6, 2015

DeBartolo Hall room 208 11:00 am.

Iddo Friedberg, Ph.D.

Associate Professor in Computational Biology,
Dept. of Veterinary Microbiology and Preventive Medicine

College of Veterinary Science,
Iowa State University

"Understanding Biological Function in Times of High Throughput and Low Output."

Dr. Iddo Friedberg

Seminar on November 6th, 2015

“High throughput biological assays are providing us with a wealth of data. However, sifting through these data to extract meaningful biological information is the challenge of early 21st Century biomedicine. The gap between the data that we have, and the useful information we extract from it is growing exponentially. I will discuss two aspects of this problem.

The first problem is that of assigning a function to a gene or a gene product. In many cases, homology searches do not yield an accurate answer, or any answer at all. For that reason, computational biologists have developed methods that consider many other attributes in the sequence's data and metadata. At the same time, it is hard to decipher which methods perform better, what “better” is, and the suitability of methods to given task: that is the second problem. To help solve this problem, we formed a consortium of the Critical Assessment of Function Annotations, a community effort to improve prediction of function from protein sequences. I will discuss the CAFA effort, and how it serves the biomedical community at large by providing an updated picture of how well we can understand biology from sequence data.”

 

Friday, October 30, 2015

DeBartolo Hall room 208 11:00 am.

Zachary T. Schafer, Ph.D.

Coleman Foundation Collegiate Chair of Cancer Biology,
Associate Professor, Dept. of Biological Sciences

University of Notre Dame


"Tumor Cell Survival During Detachment from the Extracellular Matrix: The Achilles Heel of Cancer Metastasis?"

Dr. Zachary T. Schafer

Seminar on October 30th, 2015

“Metastasis, the spread of cancer from the site of the primary tumor to distant locations in the body, is responsible for in excess of 90% of cancer deaths, yet the molecular mechanisms governing this extraordinarily complicated process remain poorly understood. It has become clear that an important barrier to metastasis is the induction of anoikis, a cell death process that is induced when epithelial cells lose attachment to the extracellular matrix (ECM). The overarching goal of my laboratory's work is to examine and characterize the biological mechanisms that permit cancer cell survival in the absence of ECM attachment. It is our hope that a better understanding of these mechanisms will reveal novel chemotherapeutic targets or approaches that may serve to compromise the survival of ECM-detached cancer cells and thus prevent tumors from successfully metastasizing. 

There are currently 4 distinct, major research projects ongoing in the lab that are all aimed at achieving the aforementioned goal:

    1. The role of ROS in the survival of ECM-detached cancer cells
    2. Carcinoma-associated fibroblast-mediated inhibition of anoikis in breast cancer cells.
    3. Tumor cell survival in inflammatory breast cancer.
    4. Oncogenic signaling involved in anoikis regulation.

During this seminar, I will focus on our most recent studies that have unveiled novel mechanisms utilized by ECM-detached cancer cells to survive and will discuss how we might take advantage of this knowledge to eliminated metastatic cancer cells.”

 

 

Friday, October 16, 2015

DeBartolo Hall room 319 2:00 pm.

 

Dimitri Krainc, M.D., Ph.D.

Chair, Department of Neurology Director, Center for Rare Neurological Diseases,
Aaron Montgomery Ward Professor

Northwestern University Feinberg School of Medicine



"Gaucher's and Parkinson's disease: how are they linked?"

 

 

Friday, October 2, 2015

DeBartolo Hall room 208 11:00 am.

 

Daniel Goldberg, M.D., Ph.D.

Professor of Internal Medicine, Infectious Diseases, and Molecular Microbiology

Howard Hughes Medical Institute



"Manipulation of host vascular biology by the malaria parasite Plasmodium falciparum."

Dr. Daniel Goldberg

Visit on October 2nd, 2015

“Cerebral malaria (CM) is a disease of the vascular endothelium caused by Plasmodium falciparum. It is characterized by parasite sequestration, inflammatory cytokine production, vasoconstriction and vascular leakage. P. falciparum produces and exports several hundred proteins into its host erythrocyte. We are interested in establishing the function of these effectors.

One such protein is histidine-rich protein II (HRPII). Plasma HRPII accumulates in the blood of patients with falciparum malaria and is a diagnostic and prognostic marker. Using a human cerebral microvascular endothelial blood-brain barrier (BBB) model, we have found that HRPII activates the inflammasome, resulting in decreased integrity of tight junctions and increased permeability. Intravenous administration of HRPII induces vascular leakage in the brains of mice, tight junction protein redistribution and increased early mortality from P. berghei experimental cerebral malaria. We propose that HRPII is a virulence factor that contributes to cerebral malaria by compromising BBB integrity.

Erythrocytes are storage reservoirs for epoxide-containing lipid signaling molecules, including epoxyeicosatrienoic acids (EETs) and epoxy​octadecenoic acids (EpOMEs).  EETs/EpOMEs function as vasodilators and anti-inflammatory modulators in the blood stream. These bioactive epoxides are hydrolyzed by epoxide hydrolases, converting them into inactive diols. We have identified and characterized two epoxide hydrolases (EH) of Plasmodium falciparum, PfEH1 and PfEH2. Both proteins are exported to the periphery of infected erythrocytes and both convert several EET regioisomers to the corresponding diols.  Manipulation of PfEH1 or PfEH2 levels in parasites results in a significant alteration in the epoxy fatty acid content of infected erythrocyte phospholipids. P. berghei has no predicted exported EHs, but chemical inhibition of the host EH enzyme reduced the percentage of mice that developed severe, cerebral malaria, without reducing parasitemia. We hypothesize that the parasite disruption of EETs/EpOMEs leads to perturbed vascular function. Both the EHs and HRPII promote favorable conditions for binding and sequestration of infected erythrocytes to the microvascular endothelium.”

 

 

Friday, September 18, 2015

DeBartolo Hall room 208 11:00 am.

 

Shaun Lee Ph.D.

Assistant Professor, Dept. of Biological Sciences

University of Notre Dame



"Fighting Microbes: Discovery and Use of Peptide- Based Bacteriocins"

Dr. Shaun Lee

Visit on September 18th, 2015

"Small peptides provide an untapped source of structural diversity much needed in pushing the frontiers of discovering new small molecule therapeutics. Peptides that are produced ribosomally by bacterial organisms are broadly known as bacteriocins. These bacteriocins comprise a large class of peptide families that have been shown to be effective as antibiotics, food preservatives, anti-infectives and anti-cancer therapeutics. With rapid advances in genomics and natural product discovery, we are currently seeing a tremendous 'explosion' in the identification and use of these ribosomally produced bacterial peptides for drug development.

One major family of peptide bacteriocins produced by bacteria are the TOMMs (thiazaole-oxazole containing modified microcins), exemplified by the hemolytic toxin known as Streptolysin S (SLS). SLS is produced by the significant human pathogen Group A Streptococcus,  a major cause of rheumatic diseases as well as invasive outcomes such as necrotizing fasciitis. Although it has been widely held that SLS exerts its lytic activity through membrane disruption, its exact mode of action has remained unknown.  We have recently demonstrated using high-resolution live cell imaging, that SLS induces a dramatic osmotic change in Red Blood Cells (RBC), leading to cell lysis. This osmotic change was characterized by SLS-mediated disruption of the major erythrocyte anion exchange protein, Band 3. Chemical inhibition of Band 3 function significantly reduced the hemolytic activity of SLS, and dramatically reduced pathology in an in vivo skin model of GAS infection.  In addition to its well-recognized role as a cytolysin, recent evidence has indicated that SLS may influence host cell signal transduction at sub-lytic concentrations during the infection process.  We identified key SLS-dependent host responses, including the initiation of specific cell death and inflammatory cascades such as Mitogen Activated Protein Kinase (MAPK) and Nuclear Factor kappa B (NFκB) signaling. 

In addition to our research efforts on the mechanims of SLS function, my research program at the University of Notre Dame continues to study mechanisms of bacteriocin production and function in diverse microorganisms, along with their roles in influencing microbial dynamics. We have identified biochemical strategies that allow for the production of diverse artificial bacteriocin libraries in high yield. These strategies will greatly expand the chemical repertoire of existing compounds, and open significant avenues into new drug research."

 


Friday, September 4, 2015

DeBartolo Hall room 319 2-3pm.

 

John F. Crowley, Chariman and CEO

Amicus Therapeutics Inc.

Hung Do, PhD, Chief Scientific Officer

Amicus Therapeutics Inc.



"When Drug Research is Personal: A Brief History of the journey toward a medicine for Pompe Disease".

John Crowley and Dr. Hung Do

Visit on September 4th, 2015

On Friday Sept 4th 2015, CRND held this season’s first Rare Disease Clinical Translational Seminar presented by John Crowley (J.D. Chairman and CEO) and Hung Do (Ph.D., Chief Scientific Officer) of Amicus Therapeutics. Amicus focuses on discovery and development of treatments for rare genetic disorders with particular interest in lysosomal storage diseases (LSD).  The research is personal because after two of his children were diagnosed with Pompe, a severe muscular glycogen storage disorder, John Crowley led a biotechnology company (Novazyme) that set on course the development of an enzyme replacement therapy (ERT) for Pompe, to treat his children’s disease.


Lysosomal storage diseases are ~50 rare inherited disorders that result from defective function of lysosomes, cellular compartments that break down large molecules (like proteins, lipids and complex sugars). When mutation renders a defect in a lysosomal protein, lysosomal degradation slows down/ becomes blocked, leading to excess accumulation of large molecules and eventually to cell and tissue malfunction.  In Pompe, the defect is in a lysosomal (protein) enzyme alpha-glucosidase (GAA), needed to break down glycogen and convert it into glucose.   A way to treat Pompe is to deliver ‘pre-made’ GAA into the blood stream from where it can be delivered to cells and into lysosomes, to rescue the defect.  But proper delivery is a complex multistep process, during which even the pre-made GAA enzyme can lose substantial structure and function and therefore potency.  Therefore Amicus Therapeutics has designed small molecule ‘chaperones’ that help the pre-made GAA enzyme better retain its structure and function.  The chaperones can also help to rescue endogenous mutant GAA protein in the patient.  A clinical trial for chaperones combined with ERT is underway for Pompe. 


We reflected on a remarkable dual partnership, with John Crowley providing the historical context and his family’s story and Dr. Hung Do presenting the recent science data on the effect of combining chaperones with enzyme replacement therapy in preclinical models. Dr. Do received his Ph.D. (in Biochemistry and Genetics) from Texas A&M University.  He did post-doctoral training at Emory University. He is an expert and industry leader on both chaperone therapy and ERT.  John Crowley received his JD from University of Notre Dame and MBA from Harvard University. He has received numerous accolades and recognition for his outstanding business leadership, social service and philanthropy.

To his family’s inspiring and well chronicled story, another extraordinary chapter was added this fall, when his daughter enrolled as a freshman, as the first student with Pompe Disease at Notre Dame.  

 

 

Of Interest...