Peter F. Davies, Ph.D.
Director, IME; Professor of Pathology & Laboratory Medicine, and Bioengineering

Mammalian cells have evolved sophisticated sensory and adaptive systems to acute and sustained changes in the mechanical environment. Their mechanical state is defined by intracellular tension arising from the organization and dynamics of cytoskeletal elements and their associated proteins, and external forces that include gravity and local forces generated by air and fluid pressure and movement. The Davies lab uses detailed analytical approaches to study intracellular mechanical systems, the interface between external forces and the cell, and the integration of these elements at the molecular level of importance to physiological and pathological mechanisms. Of particular interest are the endothelial cells that line the cardiovascular system where they are subjected to complex blood flow forces that regulate artery structure and function. The molecular signalling pathways in the endothelium arising from mechanochemical stimulation (mechanotransduction) regulate blood flow distribution and are important elements of atherosclerosis and hypertension.

Kwabena A. Boahen, Ph.D.
Assistant Professor, IME and Department of Bioengineering

Pennšs Neuroengineering effort seeks to discover functional and organizing principles of the brain---by computer modeling and by constructing brain-like machines---and to exploit these principles to solve computational tasks. Dr. Boahen joined the IME and the Bioengineering faculty in April; he has a secondary appointment in Electrical Engineering. An expert in the design of VLSI (Very Large Scale Integration) systems, Dr. Boahenšs goal is to capture both the structure and the function of neural systems in his chip designs. This effort involves using MOS devices to model nerve cell biophysics, CMOS circuits to model neuronal microcircuits, and mixed-mode, multichip, VLSI systems to model the visual and auditory systems. During his doctoral work at CalTech, he designed a chip that reproduced properties of the human retina, such as local gain control and motion sensitivity. This retinomorphic chip outperforms CCD technology as found in video cameras. Dr. Boahen is currently developing a biomorphic eyeball, that will model motor as well as sensory abilities of the eye.

Scott L. Diamond, Ph.D.
Assistant Professor, IME, Chemical Engineering, and Bioengineering

Endothelial Mechanobiology: Surgeons have long known that atherosclerotic lesions are found at sites of low and disturbed blood flow. Also, the endothelium helps match the vessel diameter to the prevailing flow rate. Our lab is investigating how genes involved in hypertension, wall thickening, and atherosclerosis are regulated by fluid flow.

Thrombolytic Therapy: Blood clot dissolving enzymes are well established for clinical use. Unfortunately, there is a limited base of knowledge by which clinical outcomes are quantitatively linked to administration regimen. We are developing large scale computer simulation and in vitro experiments to improve the design and usage of lytic agents and delivery catheters.

Gene Therapy: Gene transfer by nonviral routes is not efficient in nondividing cell. We are conducting research to understand and potentially overcome poor nuclear entry of genetic material into nondividing cells. This will be critical for virus-free gene transfer to target cells that have a low mitotic rate.

Dennis E. Discher, Ph.D.
Assistant Professor, IME, Mechanical Engineering & Applied Mechanics, Bioengineering, and Chemical Engineering

Biological cells are miniaturized machines that move and deform, adhere and grow. Determining the molecular and mechanical basis of some of these functions in select biocellular and synthetic systems is the focus of work in Dennis Discheršs laboratory. Primary tools include micromechanical devices, various microscopic techniques, and molecular biological methods. Novel methods of classical continuum mechanics and statistical physics complement the experimental approaches. Projects underway include the deformation response of blood cells and constituent molecules, the construction of artificial lipid vesicle-based blood components, and the molecular mechanisms of muscle cell adhesion and deformability. Most pressing for us with blood cells is the relation between cytoskeleton microstructure and membrane mechanics. Our vesicle-based systems are intended to elucidate basic mechanisms and responses of self-assembled interfacial structures. With muscle cells we aim to quantitatively elaborate some of the key underlying differences in healthy versus disease states, focusing on muscular dystrophy.

Daniel A. Hammer, Ph.D.
Professor, IME, Chemical Engineering, and Bioengineering

Biophysics of Cell Adhesion: Immunological defense, wound healing, blood vessel formation, and blood clotting rely critically on the proper coordination of dynamic cellular adhesive systems. The Hammer lab studies how the dynamics and strength of cell adhesion depend on the function of bioadhesion molecules, and how molecular structure codes for biomolecule function.
Virus-cell interactions: Another focus is the elucidation of molecular mechanisms of viral infection, and in particular fusion between virus and cell. A long-term goal is increasing the efficiency of infection (for gene therapy) or blocking infection (in viral mediated disease).
Soft-bio materials: Our goal is to make novel materials by integrating molecules that have bioactivity, such as bio-adhesion molecules, into colloidal and vesicular systems. Such novel materials incorporate the unique specificity of biological molecules to generate structures with novel optical and rheological properties. Another focus is to mimic the behavior of bioadhesion molecules with specially constructed polymer mimetics.

Warren S. Pear, M.D., Ph.D.
Assistant Professor, IME, and Department of Pathology and Laboratory Medicine

A major area of interest of Dr. Pear's laboratory is understanding the processes that lead to the development and differentiation of blood cells from their multipotent precursors (or stem cells). We are particularly interested in studying the processes that perturb these normal events and cause leukemia. To investigate these areas, we are taking a number of approaches that range from developing animal models of leukemia to developing quantitative assays to study cellular interactions with the extracellular matrix. A second area of research involves cell type specific delivery in gene therapy. A major obstacle to successful gene therapy is the inability to deliver the therapeutic gene to the correct target cell. We are using cells of the blood stream as a model to develop vectors that are capable of cell-type specific gene delivery by taking a number of approaches that combine individuals from both the School of Medicine and the School of Engineering.

Denise C. Polacek, Ph.D.
Senior Research Investigator, IME

Atherosclerotic lesions occur first at branches and bifurcations of the vasculature where endothelial cells experience the greatest alterations in hemodynamic shear stress. Endothelial cells are in direct communiction with each other and with other vascular wall cells via communicating pores called gap junctions. Dr. Polacek and collaborators have identified the gap junction protein connexin43 as a gene that is disregulated in vivo in atherosclerotic lesions and also in vitro in endothelial cells experiencing disturbed flow or gradients of fluid shear stress. The group is studying the genetic and functional consequences of connexin modulation in endothelial cells responding to disturbed flows. Chronic disturbed flow within lesion-prone areas of the vasculature, including vascular grafts, may result in abnormalities of endothelial cell gap junctional communication in vivo that predispose these cells to mitosis and abnormal differentiation. The long range goal is to manipulate the expressin of specific connexin proteins in seeded vascular grafts to improve graft performance.

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