BIOSKETCH OF DR. GOETZ

Education

Professional Work Experience

RESEARCH INTERESTS

Our laboratory studies the adhesion of inert particles, leukocytes and cancer cells to cellular and protein coated substrates.  We pursue these studies to achieve a fundamental understanding of various physiological and pathophysiological processes and to develop novel therapies for the treatment of disease.  Our work has three major thrusts:
 

I.  Biophysical Analysis of Adhesion Molecule Coated Microspheres.

Leukocytes (white blood cells) circulate throughout the body and fight infection.  A key component of leukocyte trafficking is leukocyte adhesion to the endothelium (the cells which line the interior of the blood vessels) in the fluid dynamic environment of the circulation.  A leukocyte which is adherent to the endothelium experiences a disruptive force due to the flow of the blood.  For the leukocyte to remain adherent, this disruptive force must be balanced by an adhesive force between the leukocyte and the endothelium.  The source of the adhesive force is non-covalent bonds which form between receptors present on the surface of the endothelium and ligands present on the surface of the leukocyte.

Our studies seek to further the understanding of the biophysics of receptor-ligand mediated adhesion.  We coat polystyrene microspheres with leukocyte ligands and study the adhesion of the ligand coated microspheres to endothelial cells under well defined in vitro fluid flow conditions.  These studies extend our understanding of various physiological and pathological processes involving leukocyte adhesion and facilitate the development of directed drug delivery agents and novel separation processes.

A portion of our work focuses on education.  Our research, and the field of bioengineering in general, uses both engineering and biological analyses.  Thus, our educational effort seeks to develop engineering and life science students who have an understanding of each others discipline.  We use our research laboratory to achieve this aim.  In addition, we have developed a biomedical engineering course which is offered to undergraduate/graduate engineering and life science students.  To overcome the differences in vocabulary used by students in these fields, a web site is being developed to support the course.
 

II.  Targeted Drug Carrier Interactions with the Endothelium under Flow.

The vascular endothelium lines the interior of the blood vessels.  Over the past decade much progress has been made in identifying the adhesion molecules which are present on the lumenal surface of the vascular endothelium.  It is now well established that the distribution of these molecules varies both spatially and temporally.  In particular, certain adhesion molecules appear to be markers for disease. Thus, it should be possible to selectively deliver therapeutic agents to sites of disease via endothelial cell adhesion molecules.

The idea is to intravascularly administer carriers (e.g. a liposome or a polymer particle) which contain a therapeutic agent.  The outer surface of the carriers would recognize an endothelial cell adhesion molecule which is selectively expressed on the target endothelial segment present at the site of disease.  Ideally these carriers would bind to the target endothelium but not bind to endothelium within healthy tissue.  To rationally develop this promising therapeutic approach, it is important to understand the biophysical mechanisms which govern targeted drug carrier interactions with the endothelium.

We use in vitro experimental techniques to address hypotheses related to targeted drug carrier interactions with the endothelium under fluid flow.  The rate of deposition and subsequent interaction of the carriers with the endothelium are governed by physical processes including reaction kinetics, adhesive mechanics, and transport; phenomena which lend themselves to an engineering analysis.  Thus, to gain an understanding of the physical processes which control the carrier - endothelial cell interactions, we conduct engineering analyses of our experimental systems.  The starting point for our analyses are mathematical models which relate endothelial cell internalization of the carriers (endocytosis) to kinetic parameters, adhesion to physical processes such as disruptive (shear) forces, and models which describe transport within flowing systems.
 

III.  Cancer Cell Arrest in the Microvasculature.

Metastasis is the process by which cancer cells from a primary tumor spread to a distant organ and form a secondary tumor.  The majority of cancer patients who succumb to cancer die due to complications involving secondary metastases rather than from the primary tumor itself.  A further understanding of the mechanisms of metastasis will lead to the development of new cancer therapies.

Hematogenous metastasis (metastasis which occurs via the circulation) begins when cancer cells dissociate from the primary tumor, invade the surrounding tissue and enter the circulation.  Once in the circulation, the cancer cells are transported to a secondary organ where they arrest in the microvasculature, migrate out of the vasculature and form a secondary tumor foci.

A critical step in the metastatic cascade is the arrest of the tumor cell in the microvasculature of a secondary organ.  This step involves a balance of forces which are mechanical and biochemical in nature.  We seek to advance the understanding of the biophysics of cancer cell arrest in the secondary organ.
 

PUBLICATIONS

Sakhalkar H., Dalal M. K., Salem A. K, Ansari R., Kiani M. F., Kurjiaka D. T., Hanes J., Shakesheff K.M. and Goetz D.J. 2003. Leukocyte Inspired Biodegradable Particles that Selectively and Avidly Adhere to Inflamed Endothelium in Vitro and in Vivo. Proc Natl Acad Sci, 100(26):15985-15900.

Yun, Y.H., D.J. Goetz, P. Yellen, W. Chen. 2004. Hyaluronan microspheres for sustained gene delivery and site-specific targeting. Biomaterials, 25(1):147-57.

Tees, D.F., D.J. Goetz. 2003. Leukocyte adhesion: an exquisite balance of hydrodynamic and molecular forces. News Physiol. Sci. 18:186-90.

Dagia, N.M., D.J. Goetz. 2003. A Proteasome Inhibitor Reduces Concurrent, Sequential and Long Term IL-1b and TNF-a Induced Endothelial Cell Adhesion Molecule Expression and Resultant Adhesion. Am J Physiol. Cell Physiol. Epub 285(4):C813-22.

Kiani, M.F., H. Yuan, X. Chen, L.A. Smith, M.W. Gaber and D.J. Goetz. 2002. Targeting Microparticles to Select Tissue via Radiation-Induced Upregulation of Endothelial Cell Adhesion Molecules. Pharm. Res. 19(9):1317-22.

E.E. Burch, V.R. Patil, R.T. Camphausen, M.F. Kiani and D.J. Goetz. 2002. The N-terminal peptide of PSGL-1 can mediate adhesion to trauma-activated endothelium via P-selectin in vivo. Blood, 100:531-8.

Prabhakarpandian, B., D.J. Goetz, R.A. Swerlick, X. Chen and M.F. Kiani. 2001. Expression and Functional Significance of Adhesion Molecules on Cultured Endothelial Cells in Response to Ionizing Radiation.  Microcirculation, 8:355-64.

Shinde Patil, V.R., C.J. Campbell, Y.H. Yuan, S.M. Slack, and D.J. Goetz. 2001. Particle Diameter Influences Adhesion under Flow.  Biophysical Journal, 80:1733-1743.

Blackwell, J.E., N.M. Dagia, J.B. Dickerson, E.L. Berg and D.J. Goetz. 2001. Ligand Coated Nanosphere Adhesion to E- and P-selectin under Static and Flow Conditions. Annals of Biomed. Eng. 29:523-533.

Dickerson, J.B., J.E. Blackwell, J.J. Ou, V.R. Shinde Patil and D.J. Goetz. 2001. Limited Specific Adhesion of Biodegradable Microspheres to E- and P-selectin under Flow. Biotechnology and Bioengineering, 73:500-509.

Lim, Y., L. Henault, D.J. Goetz, T. Yednock, C. Cabanas, F. Sanchez-Madrid, A.H. Lichtman, and F.W. Luscinskas. 2000. Expression of a4b1 Integrin Activation Epitope on CD4+ T Lymphocytes Correlates with Efficiency of Adhesion to VCAM-1 under Flow. Microcirculation. 7: 201-214.

Crutchfield, K.L., V.R. Shinde-Patil, C.J. Campbell, C.A. Parkos, J.R. Allport, and D.J. Goetz. 2000. CD11b/CD18-Coated Microspheres Attach to E-selectin Under Flow.  J. Leukocyte Biology. 67: 196-205.

Goetz, D.J., D.M. Greif, J. Shen, and F.W. Luscinskas. 1999. Cell-Cell Adhesive Interactions in an In Vitro Flow Chamber. In Protocols for Adhesion Proteins. editor: E. J. Dejana. Humana Press.

Goetz, D.J., D.M. Greif, H. Ding, R.T. Camphausen, S. Howes, K.M. Comess, K.R. Snapp, G.S. Kansas and F.W. Luscinskas. 1997. Isolated P-selectin Glycoprotein Ligand-1 Dynamic Adhesion to P- and E-selectin. J. Cell Biol.  137:509-519.

Brunk D.K., D.J. Goetz, and D.A. Hammer. 1996. Sialyl-Lewisx/E-selectin-Mediated Rolling in a Cell-Free System. Biophys. J.  71:2902-2908.

Goetz, D.J., H. Ding, W.J. Atkinson, G. Vachino, R.T. Camphausen, D.A. Cumming, and F.W. Luscinskas. 1996. A Human Colon Carcinoma Cell Line Exhibits Adhesive Interactions with P-selectin under Fluid Flow via a PSGL-1 Independent Mechanism. Am. J. Path.  149:1661-1673.

Goetz, D.J., B.K. Brandley, D.A. Hammer. 1996. An E-selectin-IgG Chimera Supports Sialylated Moiety Dependent Adhesion of Human Carcinoma Cells under Fluid Flow. Annals of Biomed. Eng. 24:87-98.

Goetz, D.J., M.E. El-Sabban, D.A. Hammer, and B.U. Pauli. 1996. Lu-ECAM-1 Mediated Adhesion of Melanoma Cells to Endothelium under Conditions of Flow. Int. J. Cancer.  65:192-199.

Hammer, D.A., L.A. Tempelman, and D.J. Goetz. 1994. Kinetics and Mechanics of Cell Adhesion under Hydrodynamic Flow:  Two Cell Systems. In Cellular Mechanics and Cellular Engineering. editors: Van C. Mow, F. Guilak, R. Tran-Son-Tay, and R. Hochmuth. Springer-Verlag Inc., New York. 121-144.

Goetz, D.J., M.E. El-Sabban, B.U. Pauli, and D.A. Hammer. 1994. Dynamics of Neutrophil Rolling Over Stimulated Endothelium in Vitro. Biophys. J.  66:2202-2209.

SOURCES OF SUPPORT