This project seeks to address the mechanisms underlying tissue integrity. We view tissue as networks of interacting cells and matrices. We hypothesize that tissue integrity results from the integration of information that arises from the dynamic interactions between the different cell types and the matrices that bind these cells together. To test this hypothesis we will focus on the kidney glomerular filtration barrier. In this system we predict that continuous information flow between a three-node loop consisting of podocytes cells, glomerular basement membrane and endothelial cells results in integrating the three entities into a single cohesive functional structure: the filtration barrier. Such information is both chemical (secreted autocrine /paracrine factors and cell/cell and cell/matrix contacts) and physical (forces arising from cell/cell and cell/matrix contacts). The information from physical and chemical sources is seamlessly integrated by intracellular signaling networks in the podocytes and endothelial cells to evoke responses that dynamically sustain the three-node loop, resulting in tissue integrity and functionality. To test these ideas we will merge 3D- computational models, nano-to-micro scale 3D fabrication and nanopatterning coupled to microfluidic devices to reconstitute a filtration barrier within the engineered device. We will use live cell imaging of signaling interactions to measure the dynamics of information flow arising from interactions between components of the reassembled tissue that give rise to the glomerular filtration barrier within the device. It is anticipated that these studies will allow us to identify general design principles to assemble functional tissues that can aid in understanding disease processes and for screening for new drugs.
The goal of this project is to understand how cells come together to form tissues. We will use the filtration barrier of the kidney cortex as our model system. We will use a combination of mathematical models and engineering approaches to develop a 3D tissue assembly.
|Azeloglu, Evren U; Hardy, Simon V; Eungdamrong, Narat John et al. (2014) Interconnected network motifs control podocyte morphology and kidney function. Sci Signal 7:ra12|
|Song, Roy S; Massenburg, Ben; Wenderski, Wendy et al. (2013) ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion. Proc Natl Acad Sci U S A 110:15437-42|
|Falkenberg, Cibele Vieira; Loew, Leslie M (2013) Computational analysis of Rho GTPase cycling. PLoS Comput Biol 9:e1002831|
|Hwangpo, Tracy Anh; Jordan, J Dedrick; Premsrirut, Prem K et al. (2012) G Protein-regulated inducer of neurite outgrowth (GRIN) modulates Sprouty protein repression of mitogen-activated protein kinase (MAPK) activation by growth factor stimulation. J Biol Chem 287:13674-85|
|Neves, Susana R (2012) Modeling of spatially-restricted intracellular signaling. Wiley Interdiscip Rev Syst Biol Med 4:103-15|
|He, John Cijiang; Chuang, Peter Y; Ma'ayan, Avi et al. (2012) Systems biology of kidney diseases. Kidney Int 81:22-39|
|Wenderski, Wendy C; Neves, Susana R (2012) Modeling of spatial intracellular signaling events in neurons. Methods Enzymol 505:105-24|
|Neves, Susana R (2011) Developing models in virtual cell. Sci Signal 4:tr12|
|Neves, Susana R (2011) Obtaining and estimating kinetic parameters from the literature. Sci Signal 4:tr8|