The thematic basis of the integrative research efforts spans around the cell, its mechanical constituents, and the mechano-transduction within cells and the cells and their surroundings.

 

Ranging in length scales from a few nanometers to many microns, inter and intra-cellular mechano-chemo-transduction signals play important roles in many aspects of cellular functions. For example, within each cell, numerous types of biomolecular nanomotors help carry out essential tasks including cellular contraction, intracellular transport of cargo around the cellular cytoskeleton, etc.

The study of these intra-cellular biomolecular mechanical components and nanomotors and how these have a direct impact on the mechanics of the cytoskeletal structure of cell and the corresponding microscale cellular processes form our first research theme, "Molecular Mechanics".

The cellular processes such as cell attachment, migration, proliferation, and cell division are critical aspects of the life-cycle of the cell. Quantitative studies of the mechanical properties of the cell and these processes form our second research theme, "Cellular Mechanics".

Finally, in the body and under physiological conditions, cells are always in mechanical communication with their environment (extra-cellular matrix) through focal adhesion points, release of chemical species, and sensing of material properties such as stiffness, etc., as they decide to die, grow or differentiate. Controlling and understanding this two-way communication in two- and three-dimensional environments is the basis of our third research theme, "Cells and ECM". The mechanical basis of signal transduction at these scales is poorly understood and only beginning to be unraveled (Vogel and Sheetz, 2006).

This project will have three thrusts:

The first will use molecular dynamics and Brownian dynamics simulations to identify atomistic details of cadherin bonds that could underlie adhesive differences between cells. Brownian dynamics and deterministic kinetic equations further link kinetic and thermodynamic properties of protein bonds to cell adhesion energies.

Second, we will use a complementary array of biophysical approaches (atomic force microscopy, surface force apparatus, micropipette manipulation, cell sorting tests) to determine the biophysical mechanism of cadherin binding, and to establish how intrinsic quantitative differences between cadherin bonds and differences in cadherin expression levels together influence cell sorting during embryogenesis. These approaches interrogate cadherins from the level of single molecules to live cells. The comparison of measured binding properties and cadherin expression levels with in vitro cell sorting outcomes further test the long-standing hypothesis that differences in intercellular adhesion energies cause cells to segregate into distinct tissues during morphogenesis.

Third, we will address biochemical and structural mechanisms of cadherin regulation. We will determine whether specific stimuli alter the intrinsic properties of cadherin bonds by inside-out signaling or induced protein conformational changes. We will focus on the impact of biochemical stimuli such as growth hormones and kinase inhibitors, to test the hypothesis that these soluble signals impinge on intracellular signaling pathways to alter the intrinsic properties of cadherin bonds, analogous to ligation-dependent changes in integrins.