Dr. Williams profile
Injury and disease in the central nervous system lead to permanent functional deficits since, unlike other organs, the CNS cannot meaningfully repair itself. Our lab focuses on two strategies to improve outcomes of nervous system injury and disease, regeneration and preservation. We use the retina as a model system because its basic circuitry is well documented, it is easily accessible for manipulations and in vivo monitoring, and the optic nerve represents the only pure white matter CNS tract making it ideal to measure axon regeneration.
To study axon regeneration, we use an optic nerve crush model. This injury severs all retinal ganglion cells (RGC) axons in the optic nerve. We then use viral vectors to overexpress or knockout specific genes in an attempt to promote RGC survival and axon regeneration after injury. Our recent work implicates new avenues for axon regeneration, including aberrant activity of local inhibitory circuits and growth factor receptor localization to RGC primary cilia. We hope to gain a deeper understanding of how these features are altered in injury and disease so that meaningful treatments can be developed.
A more straightforward approach to improving patient outcomes is to preserve tissue that would otherwise be lost. Our lab takes a basic science philosophy to therapeutic research in that we like to step back and observe events that occur after trauma or during the course of disease. To do this, we are using in vivo multiphoton microscopy to monitor RGC responses to both optic nerve crush and models of disease such as glaucoma. Since the mouse retina contains more than 40 RGC subtypes that all have different features like activity levels, metabolic demands, stress buffering capacities etc. we plan to leverage this RGC diversity as a way to determine which cellular traits underly susceptibility and survivability in various neurodegenerative conditions. Observing these discrepancies across RGC populations should provide a foundation for new therapeutic development.
Liu, Y., Wang, X., Li, W., Zhang, Q., Li, Y., Zhang, Z., Zhu, J., Chen, B., Williams, P. R., Zhang, Y., Yu, B., and He Z. A sensitized IGF1 treatment restores corticospinal axon-dependent functions (2017). Neuron 95(4), 817-833.
Nawabi, H., Belin, S., Cartoni, R., Williams, P.R., Wang, C., Latremoliere, A., Wang, X., Fu, X., Taub, D.B., Yu, B., Woolf, C.J., Liu, J.S., Gabel, C.V., Steen, J.A. and He, Z. Doublecortin-like kinases promote neuronal survival and induce growth cone reformation via distinct mechanisms (2015). Neuron 88 (4), 1-16.
Williams, P.R., Marincu, B.N., Sorbara, C.D., Mahler, C.F., Schumacher, A.M., Griesbeck, O., Kerschensteiner, M. and Misgeld, T. A recoverable state of axon injury persists for hours after spinal cord contusion in vivo (2014). Nat Commun 5 (5683).
Kleele, T., Marinkovic, P., Williams, P.R., Stern, S., Weigand, E.E., Engerer, P., Naumann, R., Hartmann, J., Karl, R.M., Bradke, F., Bishop, D., Herms, J., Konnerth, A., Kershensteiner, M., Godinho, L. and Misgeld T. An assay to image neuronal microtubule dynamics in mice (2014). Nat Commun 5 (4827).
Breckwoldt, M.O., Pfister, F.M., Bradley, P.M., Marinkovic, P., Williams, P.R., Brill, M.S., Plomer, B., Schmalz, A., St. Clair, D.K., Naumann, R., Griesbeck, O., Schwarzlander, M., Godinho, L., Bareyre, F.M., Dick, T.P., Kerschensteiner, M. and Misgeld, T. Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo (2014). Nat Med 20 (5), 555-560.