selective control of the apoptosis signaling network in heterogeneous cell populations选择性控制细胞凋亡信号网络的异构的细胞群.pdfVIP

Selective Control of the Apoptosis Signaling Network in Heterogeneous Cell Populations 1 1 2¤ 2 2 Diego Calzolari , Giovanni Paternostro , Patrick L. Harrington Jr. , Carlo Piermarocchi , Phillip M. Duxbury * 1 Burnham Institute for Medical Research, La Jolla, California, United States of America, 2 Physics and Astronomy Department, Michigan State University, East Lansing, Michigan, United States of America Background. Selective control in a population is the ability to control a member of the population while leaving the other members relatively unaffected. The concept of selective control is developed using cell death or apoptosis in heterogeneous cell populations as an example. Control of apoptosis is essential in a variety of therapeutic environments, including cancer where cancer cell death is a desired outcome and Alzheimer’s disease where neuron survival is the desired outcome. However, in both cases these responses must occur with minimal response in other cells exposed to treatment; that is, the response must be selective. Methodology and Principal Findings. Apoptosis signaling in heterogeneous cells is described by an ensemble of gene networks with identical topology but different link strengths. Selective control depends on the statistics of signaling in the ensemble of networks, and we analyze the effects of superposition, non-linearity and feedback on these statistics. Parallel pathways promote normal statistics while series pathways promote skew distributions, which in the most extreme cases become log-normal. We also show that feedback and non-linearity can produce bimodal signaling statistics, as can discreteness and non-linearity. Two methods for optimizing selective control are presented. The first is an exhaustive search m