PHYSICAL FACTORS IN B CELL ACTIN DYNAMICS AND ACTIVATION

Cells adapt to their changing world by sensing environmental cues and responding appropriately. This is made possible by complex cascades of biochemical signals that originate at the cell membrane. In the last decade it has become apparent that the origin of these signals can also arise from physical cues in the environment. Our motivation is to investigate the role of physical factors in the cellular response of the B lymphocyte. B cells patrol the body for signs of invading pathogens in the form of antigen on the surface of antigen presenting cells. Binding of antigen with surface proteins initiates biochemical signaling essential to the immune response. Once contact is made, the B cell spreads on the surface of the antigen presenting cell in order to gather as much antigen as possible. The physical mechanisms that govern this process are unexplored. In this research, we examine the role of the physical parameters of antigen mobility and cell surface topography on B cell spreading and activation. Both physical parameters are biologically relevant as immunogens for vaccine design, which can provide laterally mobile and immobile antigens and topographical surfaces. Another physical parameter that influences B cell response and the formation of the cell-cell junction is surface topography. This is biologically relevant as antigen presenting cells have highly convoluted membranes, resulting in variable topography. We found that B cell activation required the formation of antigen-receptor clusters and their translocation within the attachment plane. We showed that cells which failed to achieve these mobile clusters due to prohibited ligand mobility were much less activation competent. To investigate the effect of topography, we use nano- and micro-patterned substrates, on which B cells were allowed to spread and become activated. We found that B cell spreading, actin dynamics, B cell receptor distribution and calcium signaling are dependent on the topographical patterning of the substrate. A quantitative understanding of cellular response to physical parameters is essential to uncover the fundamental mechanisms that drive B cell activation. The results of this research are highly applicable to the field of vaccine development and therapies for autoimmune diseases. Our studies of the physical aspects of lymphocyte activation will reveal the role these factors play in immunity, thus enabling their optimization for biological function and potentially enabling the production of more effective vaccines.

THE INFLUENCE OF URBAN FORM AT DIFFERENT GEOGRAPHICAL SCALES ON TRAVEL BEHAVIOR; EVIDENCE FROM U.S. CITIES

Suburban lifestyle is popular among American families, although it has been criticized for encouraging automobile use through longer commutes, causing heavy traffic congestion, and destroying open spaces (Handy, 2005). It is a serious concern that people living in low-density suburban areas suffer from high automobile dependency and lower rates of daily physical activity, both of which result in social, environmental and health-related costs. In response to such concerns, researchers have investigated the inter-relationships between urban land-use pattern and travel behavior within the last few decades and suggested that land-use planning can play a significant role in changing travel behavior in the long-term. However, debates regarding the magnitude and efficiency of the effects of land-use on travel patterns have been contentious over the years. Changes in built-environment patterns is potentially considered a long-term panacea for automobile dependency and traffic congestion, despite some researchers arguing that the effects of land-use on travel behavior are minor, if any. It is still not clear why the estimated impact is different in urban areas and how effective a proposed land-use change/policy is in changing certain travel behavior. This knowledge gap has made it difficult for decision-makers to evaluate land-use plans and policies. In addition, little is known about the influence of the large-scale built environment. In the present dissertation, advanced spatial-statistical tools have been employed to better understand and analyze these impacts at different scales, along with analyzing transit-oriented development policy at both small and large scales. The objective of this research is to: (1) develop scalable and consistent measures of the overall physical form of metropolitan areas; (2) re-examine the effects of built-environment factors at different hierarchical scales on travel behavior, and, in particular, on vehicle miles traveled (VMT) and car ownership; and (3) investigate the effects of transit-oriented development on travel behavior. The findings show that changes in built-environment at both local and regional levels could be very influential in changing travel behavior. Specifically, the promotion of compact, mixed-use built environment with well-connected street networks reduces VMT and car ownership, resulting in less traffic congestion, air pollution, and energy consumption.