CAREER: Emergent Properties of Systems Matching in Peripheral Nervous System Development

University Of Virginia Main Campus, Charlottesville VA

Investigators

Abstract

The researchers on this project seek to understand the complex molecular signals underlying the development of neuron connections in vertebrate nervous systems. This research focuses on the role of a protein, Nerve Growth Factor (NGF) in the development of neural connections in the sympathetic nervous system (SNS), a part of the nervous system that controls the fight or flight response that is initiated by fear or stress. The studies will test how NGF, and the proteins that it interacts with, promote or inhibit neuron survival and stimulate or eliminate neuron connections during the development of the circuits that characterize the SNS. The involvement of these proteins in these developmental processes is an emerging and important area of neuroscience. Microfluidic devices and novel microscope software will be developed to automatically acquire and analyze the data. All software and microfluidic devices that are developed during the project will be freely available to the scientific community. The research will involve ten undergraduates and ten high school students over the five-year duration of the award. Additionally, the researcher will hold seminars on "thinking scientifically" for 15-20 students per year at a local high school. The impact of educational and outreach activities will be assessed using yearly surveys developed by the Curry School of Education to measure learning metrics that align with STEM-disciplines. The antagonistic relationship between NGF dependent pro-building signaling and pro-refinement signaling mediated by Tumor Necrosis Factor Receptor Family members (TNFR1, p75NTR, and DR6) will be examined. The ability of NGF to suppress destruction signaling emanating from these receptors and vice versa will be assessed in neurons from single, double, and triple TNFR1, p75NTR, and/or DR6 knockout mice. These experiments will also determine whether pro-destruction receptors require one another for cell death, branch elimination, and synapse restriction both in vitro and in vivo. If these receptors depend on one another for a particular destructive event, their physical interaction will be examined as well as whether NGF signaling influences the dynamics of this interaction as a means of inhibitory signaling. By assigning particular TNFR family members to particular destructive events and understanding how NGF suppresses each of these receptors, we are poised to gain fundamental insight into the molecular mechanisms underpinning development of the SNS.