Grant: Discovery Grants Program - Individual

Biochemical systems are often regulated by distinct mechanisms with apparently redundant effects. Using a unique toolkit of model analysis and simulation tools developed in my lab over two decades, I will study redundantly regulated gene networks to build an understanding of the physiological roles of the redundant controls. Redundancy can act as a failsafe mechanism; it can change the shape of a stimulus-response curve; it can also affect the temporal progression of a response, including its noise characteristics. Different biochemical mechanisms of redundancy may be better suited to one or another of these functions. I propose to make an intensive study of three important gene regulatory systems with different redundant control systems to develop insights into the dynamical roles of the redundancies.Cat-1 is a cationic amino acid transporter responsible for uptake of arginine and lysine, the latter an essential amino acid. Amino acid starvation results in upregulation of Cat-1 expression, proceeding in three phases: first, the translation of transcripts expressed at basal levels is turned on, which enables a rapid initial response; then, the stress-response factor ATF4 activates the transcription of the Cat-1 gene, ramping up mRNA levels; finally, a second stress-response protein, XBP1s, acts to sustain the transcriptional response. This is a very complex control system, with two distinct pathways, translational and transcriptional, for increasing expression under stress conditions. We will study this regulatory network's adaptive value by modelling the expression and transport activity of Cat-1 in a variety of nutritional environments.Bacteria frequently encounter nitric oxide (NO), either due to the mammalian immune response, or due to their own metabolism. Since NO is toxic, bacteria have defences against NO. In many bacteria, the main NO detoxification enzyme is Hmp. Hmp is only synthesized in the presence of NO. In Escherichia coli, its transcription is controlled jointly by two transcriptional repressors, FNR and NsrR. In other bacteria such as Streptomyces coelicolor, only NsrR controls the expression of Hmp. These variants will enable a direct comparison of the characteristics of redundant (E. coli) vs non-redundant (S. coelicolor) control systems.The development of internal-organ left-right asymmetry in vertebrates depends on the asymmetric expression of two proteins named Lefty and Nodal. Nodal is a left-side determinant, while Lefty is a suppressor of Nodal activity. Lefty suppresses Nodal activity by inhibiting the activating phosphorylation of the signal transduction protein Smad2. Lefty acts in three different ways to interfere with Smad2 phosphorylation. Are these redundant controls truly necessary for left-right pattern formation? If not, what evolutionary pressures sustain this redundancy?