Eric V. Shusta

Professor

3631 Engineering Hall
1415 Engineering Drive
Madison, WI 53706

Ph: (608) 262-1092
Fax: (608) 262-5434
shusta@engr.wisc.edu

Primary Affiliation:
Chemical and Biological Engineering

Additional Affiliations:
Biomedical Engineering,


Profile Summary

Non-invasive delivery of small molecule pharmaceuticals and biopharmaceuticals (protein pharmaceuticals) to the brain is hindered by the presence of the blood-brain barrier (BBB). This impermeable barrier, comprised of endothelial cells, separates the bloodstream from the interstices of the brain. Unless a molecule satisfies the dual criteria of having a small molecular size of less than 600 daltons and a high degree of lipid solubility, it will not cross the BBB. Because of these constraints, greater than 98% of small molecule pharmaceuticals do not cross the BBB and no biopharmaceuticals can cross this barrier. We are focused on overcoming this barrier through the development of non-invasive delivery methods that target drugs to the brain for the treatment of neurological diseases.

Traditionally, the design of neuropharmaceuticals has been chemistry-driven and has relied on the manipulation of small molecule compounds to satisfy the size and lipid solubility requirements. However, molecular engineering techniques allow us to take a more robust approach and employ endogenous transport mechanisms present at the BBB as a means to shuttle drug cargo from the blood to the brain. These cellular transport systems can be targeted using the exquisite specificity of antibodies that are in turn linked to a drug payload that can include small molecule pharmaceuticals, biopharmaceuticals, or even DNA therapeutics. We are therefore interested in the discovery of novel transport systems and cognate antibody targeting molecules, and we design high throughput selections that serve this purpose. Along these lines, we are also working to optimize the process for producing large amounts of therapeutic antibodies and proteins to meet the eventual demands of clinical application.

We are also interested in developing an in vitro model of the BBB that accurately mimics the in vivo characteristics of the BBB. An in vitro BBB model would permit the combinatorial screening of drug candidates and drug-targeting strategies, a process that is not amenable to an in vivo system. When the endothelial cells that make up the BBB are cultured in vitro, however, changes in gene and protein expression occur thereby altering the permeability characteristics and integrity of the in vitro model. We investigate these changes using genomics and proteomics techniques in an attempt to understand how gene and protein expression must be modulated to yield properties representative of the in vivo BBB. We then work to leverage this information for the development of novel in vitro models that possess more in vivo-like qualities.

Education

  • BS, UW-Madison
  • MS, PhD, University of Illinois at Urbana-Champaign

Research Interests

  • brain drug delivery
  • blood-brain barrier engineering
  • biopharmaceutical design
  • protein engineering

Awards, Honors and Societies

  • H.I. Romnes Faculty Fellowship (2013)
  • American Chemical Society BIOT Division Young Investigator Award (2013)
  • Editorial Board-Fluids and Barriers of the CNS (2010-)
  • Polygon Engineering Council Outstanding Instructor Award (2007)
  • Governing Council, International Brain Barriers Society (2006-)
  • NSF CAREER Award (2003-2008)
  • Camille & Henry Dreyfus New Faculty Award(2001-2006)
  • NIH Blood-Brain Barrier Training Fellowship (1999-2001)

Publications

SELECTED PUBLICATIONS

  • Lippmann E.S., Al-Ahmad A., Palecek S.P., Shusta E.V., Modeling the Blood-Brain Barrier Using Stem Cell Sources, Fluids and Barriers of the CNS, online, Jan 9, 2013.
  • Lippmann E.S., Azarin S.M., Kay J.E., Nessler R.A., Wilson H.K., Al-Ahmad A., Palecek S.P., Shusta E.V., Human Blood-Brain Barrier Endothelial Cells Derived from Pluripotent Stem Cells, Nature Biotechnology, 30, 783-791, 2012.
  • Tillotson B.J., de Larrinoa I.F., Skinner C.A., Klavas D.M., Shusta E.V., Antibody Affinity Maturation Using Yeast Display with Detergent-Solubilized Membrane Proteins as Antigen Sources, Protein Engineering Design Selection, online, Oct 30, 2012.
  • Lippmann E.S., Weidenfeller C., Svendsen C.N., Shusta E.V., Blood-Brain Barrier Modeling with Co-cultured Neural Progenitor Cell-derived Astrocytes and Neurons, Journal of Neurochemistry, 119, 507-520, 2011.
  • Agarwal N., Lippmann E.S., Shusta E.V., Identification and Expression Profiling of Blood-Brain Barrier Membrane Proteins, Journal of Neurochemistry, 112, 625-635, 2010.
  • Cho Y.K., Shusta E.V., Antibody Library Screens Using Detergent-Solubilized Mammalian Cell Lysates as Antigen Sources, Protein Engineering Design Selection, 23, 567-577, 2010.
  • Pavoor T.V., Cho Y.K., Shusta E.V., Development of GFP-based Biosensors Possessing the Binding Properties of Antibodies, Proceedings of the National Academy of Sciences, USA, 106, 11895-11900, 2009.
  • Agarwal N., Shusta E.V., Multiplex Expression Cloning of Blood-brain Barrier Membrane Proteins, Proteomics, 9, 1099-1108, 2009.
  • Huang D., Gore P., Shusta E.V., Increasing Yeast Secretion of Heterologous Proteins by Regulating Expression Rates and Post-Secretory Loss, Biotechnology and Bioengineering, 101, 1264-1275, 2008.
  • Calabria A.R., Shusta E.V., A Genomic Comparison of In vivo and In vitro Brain Microvascular Endothelial Cells, Journal of Cerebral Blood Flow and Metabolism, doi: 10.1038/sj.jcbfm.9600518, 2007.
  • Wang X.X., Cho Y.K., Shusta E.V., Mining a Yeast Library for Brain Endothelial Cell-Binding Antibodies, Nature Methods, 4, 143-145, 2007.
  • Wentz A.E. and Shusta E.V., A Novel High Throughput Screen Reveals Yeast Genes that Increase Heterologous Protein Secretion, Applied and Environmental Microbiology, 73, 1189-1198, 2007.
  • Weidenfeller C., Svendsen C.N., Shusta E.V., Differentiating Embryonic Neural Progenitor Cells Induce Blood-Brain Barrier Properties, Journal of Neurochemistry, 101, 555-565, 2007.
  • Calabria A.R., Weidenfeller C., Jones A.R., deVries H.E., Shusta E.V., Puromycin-Purified Rat Brain Microvascular Endothelial Cell Cultures Exhibit Improved Barrier Properties in Response to Glucocorticoid Induction, Journal of Neurochemistry, 97, 922-933, 2006.
  • Hackel B.J., Huang D., Bubolz J.C., Wang X.X., Shusta E.V., Production of Soluble and Active Transferrin Receptor-Targeting Single-Chain Antibody using Saccharomyces cerevisiae, Pharmaceutical Research, 23, 790-797, 2006.
  • Wang X.X., Shusta E.V., The Use of scFv-Displaying Yeast in Mammalian Cell Surface Selections, Journal of Immunological Methods, 304, 30-42, 2005.
  • Huang D., Shusta E.V., Secretion and Surface Display of Green Fluorescent Protein Using the Yeast Saccharomyces cerevisiae, Biotechnology Progress, 21: 349-357, 2005.
  • Also see a complete list of publications at http://www.ncbi.nlm.nih.gov/pubmed/?term=shusta+ev

Courses

Fall 2014-2015

  • BME 790 - Master\'s Research and Thesis
  • BME 399 - Independent Study
  • CBE 489 - Honors in Research
  • CBE 790 - Master\'s Research or Thesis
  • CBE 699 - Advanced Independent Studies
  • CBE 990 - Thesis-Research
  • CBE 890 - Pre-Dissertator\'s Research
  • CBE 599 - Special Problems
  • CBE 311 - Thermodynamics of Mixtures
  • Profile Summary

    Non-invasive delivery of small molecule pharmaceuticals and biopharmaceuticals (protein pharmaceuticals) to the brain is hindered by the presence of the blood-brain barrier (BBB). This impermeable barrier, comprised of endothelial cells, separates the bloodstream from the interstices of the brain. Unless a molecule satisfies the dual criteria of having a small molecular size of less than 600 daltons and a high degree of lipid solubility, it will not cross the BBB. Because of these constraints, greater than 98% of small molecule pharmaceuticals do not cross the BBB and no biopharmaceuticals can cross this barrier. We are focused on overcoming this barrier through the development of non-invasive delivery methods that target drugs to the brain for the treatment of neurological diseases.

    Traditionally, the design of neuropharmaceuticals has been chemistry-driven and has relied on the manipulation of small molecule compounds to satisfy the size and lipid solubility requirements. However, molecular engineering techniques allow us to take a more robust approach and employ endogenous transport mechanisms present at the BBB as a means to shuttle drug cargo from the blood to the brain. These cellular transport systems can be targeted using the exquisite specificity of antibodies that are in turn linked to a drug payload that can include small molecule pharmaceuticals, biopharmaceuticals, or even DNA therapeutics. We are therefore interested in the discovery of novel transport systems and cognate antibody targeting molecules, and we design high throughput selections that serve this purpose. Along these lines, we are also working to optimize the process for producing large amounts of therapeutic antibodies and proteins to meet the eventual demands of clinical application.

    We are also interested in developing an in vitro model of the BBB that accurately mimics the in vivo characteristics of the BBB. An in vitro BBB model would permit the combinatorial screening of drug candidates and drug-targeting strategies, a process that is not amenable to an in vivo system. When the endothelial cells that make up the BBB are cultured in vitro, however, changes in gene and protein expression occur thereby altering the permeability characteristics and integrity of the in vitro model. We investigate these changes using genomics and proteomics techniques in an attempt to understand how gene and protein expression must be modulated to yield properties representative of the in vivo BBB. We then work to leverage this information for the development of novel in vitro models that possess more in vivo-like qualities.


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