The laboratory’s research is organized along three main themes:
(I) Post-mitochondrial regulation of programmed cell death in the mammalian CNS.
(II) EphB-mediated control of neural connectivity in the mammalian CNS.
(III) Development and analysis of small molecule therapeutic to PCD.
(I) Programmed cell death:
During neural development and following many forms of injury, damaged cells are eliminated through a cell autonomous process known as apoptosis or programmed cell death (PCD). Abnormal regulation of PCD is known to occur in a wide variety of cancers and neurodegenerative disorders such as Amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s chorea. PCD also plays an important role in acute injury states such as spinal cord injury and stroke. Understanding the molecular mechanisms which regulate PCD is therefore a critical feature of enhancing functional recovery following injury. The laboratory is investigating molecular interactions which are common to many forms of PCD/apoptosis. This research is aimed at characterizing key protein-protein interactions which control neuronal injury and survival following CNS insult. Our emphasis is on those neural circuits which govern motor control.
(II) Axon guidance:
Meaningful functional recovery within the injured adult central nervous system requires both neuronal survival and appropriate re-innervation of injured neurons to neural targets. In order better understand the process of local axon guidance during mammalian development and following CNS injury we are investigating a family of axon guidance molecules known as the EphB family. We have previously demonstrated that these receptor tyrosine kinases play important roles in regulating the organization of several regions of the CNS, as well as being critical regulators of dynamic neural remodeling. We are currently attempting to understand the role which Eph receptors play in regulating several novel features of motor and sensory control in the CNS.
(III) Molecular Therapeutics:
Through the use homologous gene targeting, the role which a specific gene plays in a given signaling process can determined in vivo. Over the past decade, our investigations have allowed us to identify key molecular interactions which govern specific forms of neural cell death. Modified variants these proteins can be introduced in a stable manner into cell lines where the dynamic nature of their interaction can be investigated in real time. Using such methodologies we have developed high throughput screening assays to assess the ability of thousands of small molecular interactors to influence specific elements of protein function with respect to cell injury. At present we have identified compounds capable of altering the pattern specific molecular interactions relevant to PCD. We are currently investigating the detailed mechanism of these agents and their ability to alter PCD in vivo.
Research topics by field: Molecular and Cellular Neuroscience – Biochemistry of programmed cell death and axon guidance in neurons in the central nervous system. Developmental Neuroscience – Regulation of CNS apoptosis, Eph-mediated axon guidance, motor development in mammals. Neurobiology of Disease – Response and regeneration of the CNS following injury, murine models of human disease. Neurogenetics – Conditional gene knockouts, modification of embryonic stem cells. Neuroimaging– In vivo / ex vivo optical imaging of the CNS, MRI, electromyography, electron microscopy. Neuroanatomy – Stereotactic neurosurgery (rodent models of human disease), Development of variational atlases of mouse brain.
Investigational methods utilized: Homologous (ES/iPS) gene targeting, ex vivo CNS slice and primary neuronal culture, gene transduction methods (biolistic, microinjection, electroporation), stereotactic and laser-based microsurgical methods, in vivo methods of neural tracing, analysis of neuroanatomy / neural morphometry in rodents, molecular biology and biochemistry.