Quantitative Systems Pharmacology is well suited to determine the molecular pathogenesis of neurodegeneration (ND). Our efforts have focused on understanding disease mechanisms of Huntington’s Disease (HD), traumatic brain injury (TBI), and Alzheimer’s Disease (AD). In a long-standing collaboration with Ivet Bahar, PhD, Chair of the Department of Computational and Systems Biology and associate director of UPDDI, Robert Friedlander, MD, Chair of the Department of Neurosurgery, and the Chemical Genomics Center team at the National Center for Advancing Translational Sciences (NCATS), we have identified several potential neuroprotective pathways for HD. We have extended this work in a collaboration with Ilyas Singec, MD, PhD, Director of the NCATS STEM Cell Translation Lab, to optimize iPSC technologies for neuronal differentiation, and advance the development of 3D brain models for HD and other ND diseases. We also have a collaboration with James Kozloski, PhD, leader of IBM’s Department of Computational Neuroscience and Multiscale Brain Modeling group, combining our approach with their single cell neuronal modeling to predict electrophysiological phenotypes in medium spiny neurons involved in HD resulting from drug application.
Epidemiological studies have long implicated TBI as a major risk factor for future development of neurodegeneration. We are collaborating with David Okonkwo, MD, PhD, Director of the Neurotrauma Clinical Trials Center at UPMC, Pat Kochanek, MD, Director of the SAFAR Center, and Phil LeDuc, PhD, Director of the Center for Mechanics and Engineering of Cellular Systems at Carnegie Melon University, to identify the mechanisms responsible for the neurodegenerative TBI phenotype and potential drugs to protect against TBI induced ND. This project is funded through a CURE grant from the Commonwealth of PA.
In collaboration with Amantha Thathiah, PhD, in the Department of Neurobiology, we are merging phenotypic screening with computational inference to deconstruct Aβ-induced toxicities into targetable and interacting pathogenic and protective pathways in a project funded by National Institute on Aging. Our goal is to efficiently identify drug combinations that stave off Aβ-induced toxicity in human iPSC-derived AD cell models.
Key faculty for the ND programs are D. Lansing Taylor, PhD , Andrew Stern, PhD, Timothy Lezon, PhD, and Mark Schurdak, PhD, all from the Department of Computational and Systems biology and the UPDDI.