Neurodegenerative Diseases

Our HD QSP program is working to understand the mechanisms of HD progression starting with readily available established animal cell models, and moving to a more physiologic 3D human microphysiological systems (MPS) HD experimental model.
Identification of mechanisms responsible for TBI induced neurodegeneration and development of drugs to protect against neurodegeneration in TBI, Huntington’s disease and Alzheimer’s disease.

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).  

Epidemiological studies have long implicated TBI as a major risk factor for future development of neurodegeneration.  Alterations in synaptic vesicle homeostasis are believed to cause devastating impairments in brain function after TBI.  We are collaborating with Shaun Carlson, PhD, in the Department of Neurological Surgery, to generate a dynamic network map of TBI progression and computationally model synaptic dysfunction mechanism of TBI as a novel therapeutic approach for TBI.  In another collaboration with David Okonkwo, MD, PhD, Director of the Neurotrauma Clinical Trials Center at UPMC, Patrick 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,  we have identified  several potential mechanisms responsible for the neurodegenerative TBI phenotype and potential drugs to protect against TBI induced ND. This project was funded through a CURE grant from the Commonwealth of PA.  

Past Program Collaborations

Through a long-standing collaboration with the department of Computational and Systems BiologyRobert 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. This work was extended in a collaboration with Ilias 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 entered into  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. 

A pathway network has been computationally inferred based on the differential expression of genes in primary rat neurons in response to mechanical stretch injury, which mimics TBI. 137 pathways are predicted to be either activated (red) or inhibited (blue) in response to injury. Compounds that modulate these pathways are tested to understand the role of the pathways in the injury response, leading to identifying therapeutic strategies.

Key faculty for the ND programs are D. Lansing Taylor, PhD , Andrew Stern, PhD, and Mark Schurdak, PhD, all from the Department of Computational and Systems Biology and the UPDDI.

Click here and include “ND” in the Additional Gift Instructions to support development of therapeutics for TBI and neurodegeneration