Analysis of Mechanisms of Biochemical Homeostasis

Grant Number: DMS-061670    
Funding Agency: NSF
PI: Michael C Reed Co-PIs: Fred Nijhout and Jon Mattingly
Effective Dates: 2006/09-2009/08
Amount: $349,999

Description: The properties of cells depend on a large, highly interconnected, heirarchical network of genetic and biochemical interactions whose behaviors depend on a great many time varying inputs. Some of these inputs induce large responses in local areas of the network and many of these local networks have been the subject of biological and mathematical investigations. Insufficient attention has been paid to fact that these local networks do not exist in isolation but are interconnected with many other such local networks in the cell. Because the global gene-biochemical network is so highly interconnected, one would expect that large changes in one local network would propagate and potentially disrupt the ``normal'' functions of other local networks. This raises the important biological question of how the cell can maintain its myriad normal functions despite large changes in certain small subnetworks. Understanding the mechanisms producing homeostasis requires understanding the general principles governing the propagation of fluctuations through complex metabolic reaction networks. This raises challenging mathematical issues since the networks have complicated topology and the reaction dynamics are often nonlinear. The PIs will analyze how random fluctuations are attenuated in large complex networks (both random and deterministic) with homogeneous local reactions dynamics. They will also investigate the regulatory properties of specific biochemical mechanisms in small inhomogeneous networks that stabilize particular concentrations and fluxes against outside perturbations. The proposed work builds on previous work of the PIs who discovered a range of novel regulatory mechanisms that produce homeostasis in a complex metabolic reaction network, one-carbon metabolism..