 |
 
|
|
Faculty > Daniel A. Hammer Daniel A. Hammer
Alfred G. and Meta A. Ennis Professor of Bioengineering
B.S.E., Chemical Engineering, Princeton University, 1982 email:
Current Focus of Research The focus of the Hammer laboratory is on developing a fundamental understanding of cell behavior, specifically cell contact phenomena. Specific areas of interest are cell-substrate adhesion, cell mechanotransduction, cell motility, artificial cells and vesicles, and biologically-inspired self-assembling materials. Cell Adhesion In cell adhesion, or primary focus has been on the dynamics of adhesion mediated by blood-borne cells to surfaces in the microvasculature under flow. This type of adhesion is ubiquitous in physiology – it is displayed by leukocytes to enter tissues during inflammation, stem cells to home to bone marrow to regenerate tissues and during transplants, and metastasizing cancer cells to enter secondary tumor sites . We have developed novel experimental and theoretical tools to understand and manipulate this type of adhesion. Our cell-free colloidal mimetics allow us to recreate leukocyte adhesion by attaching putative adhesion ligands to beads, and focus on elucidating molecular mechanisms without the confounding effects of cell rheology, roughness or signaling. Recently, we have performed single molecule measurements of the relationship between receptor-ligand bond dissociation and force, and related these measurements to the macroscopically observed dynamics of adhesion (in collaboration with Evan Evans, Boston University). Also, we have shown that stem cells use similar molecules as leukocytes (selectins) for trafficking, with the most naïve cells the best able to home and traffick to bone marrow stroma. This has led to ongoing work on the technological innovation of fractionating stem cells by differential adhesive interactions. Adhesive and Multi-particle Adhesive Dynamics We have used computational techniques to relate single molecule properties to adhesion. We have developed adhesive dynamics, a computer simulation of adhesion that allows us to relate molecular properties of adhesion molecules to dynamic states of adhesion, thus answering the fundamental question of why diverse molecules have evolved for specific tasks in the immune system. A further recent development is the extension of the simulations to include hydrodynamic and biospecific interactions between particles. This methodology, called multiparticle adhesive dynamics (MAD), can be used to simulate the collective behavior of cells in dense systems, such as blood. The simulations and confirming experiments have shed fundamental insights into how cell concentration and contact can regulate the dynamics and extent of adhesion in blood vessels. The next challenge is to incorporate intracellular signal transduction networks within these mechanically accurate models to understand the dynamic process of adhesion phenotype switching that occurs in many trafficking cells. Artificial Cells We have extended the theme of cell mimicry to make novel cell-like materials that can be used for technological purposes, such as drug or gene delivery. We have attached adhesion ligands to porous microspheres as drug delivery carriers that can exploit adhesion-based inflammatory pathways. We are also interested in novel materials that can be made from, incorporate, or mimic biological functionality. With Dennis Discher (MEAM/Penn) and Frank Bates (CEMS/Minnesota), we have made a class of giant vesicles from diblock copolymers, with substantially enhanced materials properties compared to phospholipid vesicles. We are pursuing applications of these polymer vesicles to drug delivery and for molecular and cellular imaging. Viral Infection We are also interested in the molecular mechanisms by which viruses attach to and infect cells. We have performed theoretical analyses to understand the avidity of virus-cell interactions. We have applied our methods to understand how viral infection may be blocked by soluble receptors. After infection, viruses enter cells via fusion between their outer envelope and the membrane of intracellular vesicles. This fusion is mediated by proteins. To understand the chemical and mechanical requirements on protein and lipid to mediate fusion, we have built a micropipette aspiration assay of membrane fusion in which exchange between vesicles can be monitored with fluorescent dyes. Biofunctional Materials We are also interested in making colloidal materials and structures that are crosslinked by biological adhesion molecules. These materials would be novel because they are driven by attractive interactions, could be used to make binary component colloidal materials with precision, and would have novel structures and rheology, owing to the unique properties of the biological molecules that crosslink them. The materials are made and characterized in collaboration with Dave Weitz (Physics/Harvard). Mechanotransduction and Tissue Self-assembly We have begun to explore the factors that influence tissue self-assembly. Using angiogenesis as a model, we are exploring the role of differential adhesion in controlling the self-assembly of microvascular precursors. In collaboration with Micah Dembo (Boston University), we are developing force traction microscopies for observing endothelial cell decisions during two-dimensional angiogenesis, and how it is related to substratum adhesive strength, matrix elasticity, and matrix micropatterning. We are further using genomic profiling (with Peter Davies, Penn) to assess switching of genes during endothelial cell decision making, in both angiogenesis and early inflammation. Further, we are interested in developing models for adhesion strength and motility that incorporate accurate mechanics of tape peeling, cytoskeletal activity and signal transduction. Honors and Awards:
C. Reinhart-King and D.A. Hammer. (2006). “Traction Forces Exerted by Adherent Cells,” in Advances in Cellular Engineering: Micromechanics at the Biomolecular Interface. Edited by Michael R. King. Publisher, Elsevier Academic Press, Burlington, MA. p 3-24. Yee, Kelly L., and D. A. Hammer, “A Computational Model of Integrin-mediated Signaling through MAP-kinase Pathways,” under revision, Biophysical Journal. P. Peter Ghoroghchian, Paul R. Frail, Kevin P. Davis, Frank S. Bates, Michael J. Therien, and D.A. Hammer, (2006). “Bioresorbable Vesicles Formed through Spontaneous Self-Assembly of Amphiphilic Polyethyleneoxide-Block-Polycaprolactone,” Macromolecules 39(5); 1673-1675. John J. Lin, P. Peter Ghoroghchian, Ying Zhang, and D.A. Hammer, (2006) “Adhesion of Antibody-Functionalized Polymersomes,” Langmuir 22(9); 3975-3979. Lee A. Smith, Helim Aranda-Espinoza, Jered B. Haun, and D. A. Hammer, (2006). “Interplay Between Shear Stress and Adhesion on Neutrophil Locomotion”, revised and resubmitted, Biophysical Journal. Blank, C., Smith, L.A., Hammer, D.A., Fehrenbach, M. , DeLisser, H.M., Perez, E., Sullivan, K. E. (2005) ”Recurrent infections and immunologic dysfunction in two siblings with congenital disorder of glycosylation 1a (CDG1a),” submitted, Journal of Inherited Metabolic Diseases. Lauren R. Pepper, D.A. Hammer and Eric T. Boder. (2006) “Rolling Adhesion of ?L I-domain Mutants Decorrelated from Binding Affinity”, accepted, Journal of Molecular Biology. Kheya Sengupta, Helim Aranda-Espinoza, Lee A Smith, Paul A. Janmey, and D. A. Hammer. (2006). “Spreading of neutrophils: from activation to migration,” submitted, Biophysical Journal. Kelly E. Caputo, Dooyoung Lee, Michael R. King, and Daniel A. Hammer (2006). “Adhesive Dynamics Simulations of the Shear Threshold Effect for Leukocytes,” submitted, Biophysical Journal. Hong Chen, Zhiying Zou, Kendra L. Sarratt, Dian Zhou, MaoZhen Zhang, Eric Sebzda, D.A. Hammer and Mark L. Kahn. (2006). “In vivo beta 1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines,” Genes & Development 20:927-932. Christian, Natalie A., Michael C. Malone, Shraddha S. Ranka, Guizhi Li, Paul R. Frail, Kevin P. Davis, Frank S. Bates, Michael J. Therien, P. Peter Ghoroghchian, Carl H. June & D. A. Hammer, (2006) “Tat-Functionalized Near-Infrared Emissive Polymersomes for Dendritic Cell Labeling,” submitted, Bioconjugate Chemistry. Swift, D.G., and D.A. Hammer, “Kinetics of antigen-antibody-mediated cell adhesion in Couette flow”, under revision, Langmuir. Swift, D.G, and D.A. Hammer, “Rate-based cell separations in a linear shear field,” under revision, Biotechnology and Bioengineering. Swift, D.G., R. Posner, and D.A. Hammer. “Kinetics and dynamics of adhesion mediated by low affinity antigen-antibody interactions”, under revision, Biophysical Journal.
|
|
|
|
|