Grant: Discovery Grants Program - Individual

Living creatures have length- and time-scales ranging from the molecular to the organismal. We often have genetic control over molecular details, but we are ultimately interested in organismal function. Coarse-grained models can bridge between these scales. We will develop new coarse-grained models for each of three important biological systems. We will ""right size"" each model so that it is able to confront a variety of experimental behaviors while remaining usefully tractable.*** Collagen plays essential roles from tendons to the cornea. We will develop a combined structural and mechanical model of fibrillar collagen. Periodic structure along the fibril length will be included with methods developed for coarse-grained studies of metallic crystals, while the mechanical contributions of cross-linking will be treated with methods developed for liquid-crystalline rubbers. Our improved understanding of how to control the mechanical properties of fibrils will facilitate better design of collagenous materials.*** Living organisms age and die. We will further develop a network-based model for organismal aging and mortality. We will explore why it works, how we can better test it with observational data, and how we can use it to improve individual predictions of aging and mortality. We will first determine the evolutionarily-optimal network topology. We will then compare it to the network inferred from observational data using Bayesian statistics. We will use these networks to examine when damage could be repaired before it leads to further damage, for a variety of modelled organisms. The result will be a deeper understanding of how aging, damage, and mortality intertwine; and how much they can be adjusted.*** Pathogenic bacteria can invade and reproduce within layers of host cells. We will examine what determines the propagation of bacteria in host-cell layers. To do this, we will start with computational models of cell layers. From experimental video-microscopy, we will use computational image-analysis to parameterize detailed models of the invasion and propagation of bacteria between individual cells. These detailed models will be used to control bacterial infection, growth, and transmission within our cell-layer models. The result will allow us to bridge between simplified but convenient experiments in petri-dishes and more realistic but difficult experiments within living organisms.*** We will build models of stochastic, non-linear, and non-equilibrium biological systems at appropriate coarse-grained scales. We will do this in collaboration with experimental colleagues in order to confront, understand, and expand available data. These models will serve as bridges between the microscopic, molecular detail that can be experimentally controlled and the macroscopic behavior that is important to us. Our work will unify understanding of these systems, speed discovery of novel behavior, and facilitate our ability to modify these important biological systems. *****