MOLECULAR and cellular MECHANISMS of NEURONAL Disorders
Our research mission is to identify molecular and cellular mechanisms of neurological disorders using human cell and animal model systems.
We currently focus on two goals: 1) Modeling neurodevelopmental disorders and neurotrauma in human cellular systems to understand the pathophysiology of different brain cell types; 2) The identification of the cellular and molecular and cellular mechanisms of traumatic brain injury (TBI) responsible for the increased risk of neurodegenerative disease later in life using pre-clinical mouse models of TBI.
1. Modeling Neurological Disorders in in human cellular systems
My laboratory uses human induced pluripotent stem cells (hiPSCs) to create human cell cultures to model CNS trauma and disease. We use these in vitro platforms to investigate molecular mechanisms of pathology and to identify disease-modifying molecules for therapeutic development. Current projects in the laboratory include the use of CRISPR/Cas9 edited and patient-derived hiPSCs to identify human cortical neuron-specific substrates of the E3 ligase UBE3A. Mutations in UBE3A account for 85-90% of cases of Angelman Syndrome (AS), a complex neurological disorder characterized by developmental delay, intellectual disability, speech impairment, seizures and ataxia.
2. Molecular and Cellular Mechanisms of Traumatic Brain Injury Pathology
My laboratory is applying state-of-the-art spatial and single cell transcriptomic approaches to well characterized open- and closed-head TBI mouse models of mild contusion injury to identify the molecular pathologies of traumatic brain injury.
Guided by preliminary data, we are currently pursuing two research paths focusing on the distinct molecular features of damaged white and grey matter in the contused brain:
(i) We are investigating the role of peripheral immune cell signaling on the evolution of glial subpopulations in vulnerable white matter (WM) post-injury. This project is based on preliminary data identifying WM glial cell states in TBI mice that have been reported in mouse models of neurodegenerative disease such as Alzheimer’s disease (AD). Our hypothesis is that CNS damage and disease initiate shared pathological glial cell state changes.
(ii) A second project is testing the hypothesis contusion initiates the expression of transcriptional regulators and downstream kinases of the neuronal stress sensor pathway in outer layer neocortical neurons that can be manipulated to improve neuronal resiliency post-trauma.
The overall goal of both of these projects is to identify novel therapeutic targets to improve TBI outcomes through a more detailed understanding of spatiotemporal patterns of molecular pathology following a TBI.