DMS/NIGMS 1: Multiscale modeling of Notch signaling during long-range lateral inhibition
NIH
CLARKSON UNIVERSITY
The spatiotemporal distribution of morphogens contributes to the organized development of tissues and organs.  One model of morphogen distribution is active transport, which includes cell based mechanisms like signaling  filopodia. Signaling filopodia facilitate contact between distant cells in order to allow signaling to occur, and support  several cell signaling paradigms during development. The proposed project will use multi-scale modeling and  biological experiments to test the hypothesis that Notch signaling occurs via filopodia-filopodia mediated cell-cell  contacts in vivo. This hypothesis will be tested in three objectives. (1) Investigate the mechanism of Notch activation  on filopodia. A mechanical model of distinct modes of filopodia interactions will be used to quantify the forces  generated during filopodia mediated signaling to identify the most likely mechanism for Notch activation. (2)  Determine how Notch signal is relayed to the cell body. A mathematical model of filopodia in the presence of  diffusion and active transport of signals will be developed to quantify the relative importance of each mechanism.  We will support our model with genetic approaches and quantitative live imaging. (3) Create a multi-scale vertex  model of Notch signaling during bristle cell patterning. We will combine the above molecular and cellular sub_x0002_models of Notch signaling to create a truly multi-scale vertex model of the patterning thorax. This framework will  support an in silico, real-time investigation of patterning dynamics via signaling filopodia to identify potential  molecular regulators of this process. The success of this proposal will result in a foundational understanding of the  mechanisms that drive long-range lateral inhibition during tissue patterning. We will introduce the first multi-scale  mechanical model of the fly thorax that allows for cell-driven dynamics of filopodia and real-time activation of  Notch. The experimental work proposed here addresses a major gap in our understanding of tissue development  and homeostasis: how active cell processes contribute to the distribution and activation of signals. A major challenge for the organized development and homeostasis of tissues and organs is the correct  spatial and temporal distribution of signaling molecules. Achieving a correct tissue organization is critical as  defects in patterning can lead to human disorders and disease. This project will take both multi-scale  mathematical modeling and experimental approaches to investigate how the signaling receptor Notch is  distributed and activated by active cell processes during lateral inhibition-mediated tissue patterning events.
Non-SBIR/STTR