The objective of this proposal is to cultivate the abilities of the principal investigator as a developmental neurobiologist, teacher, and clinician, interested in neonatal neurology and early cortical development. Preparation of the principal investigator as a scientist and clinician will include: 1) intensive research training, focused on investigations of the molecular interactions involved in formation of the neocortex, 2) exposure to a rich academic and intellectual environment through participation in developmental neurobiology seminars and journal clubs, formal laboratory meetings, and clinical neurology seminars, and through recurring interactions with several established scientists and clinicians, 3) clinical exposure to patients with neurodevelopmental disorders in a setting that will allow enhancement of clinical skills and acquisition of the necessary tools to become an excellent teacher. The scientific research protocol will test the hypotheses that: 1) Fibronectin (via integrin-mediated binding) and the neuron-glia ligand, astrotactin, are vital participants in the migration of young neurons from their origin in the ventricular zone to their residence in the neocortex. 2) Developing cortical neurons display differential responses to neurotrophins that are both age-dependent and layer specific. 3) Cortical neurons express receptors specific for those neurotrophins to which they respond. 4) Cortical neurons are dependent on specific neurotrophins for proliferation, migration, maturation, and survival. To test these hypotheses, the principal investigator has developed an in vitro organotypic slice preparation that will allow perturbation of the neuron- glial and neuron-ECM interactions and quantitative assessment of the effects on migration. These slices will also be used to study the effects of neurotrophins in cortical development. Additionally, the principal investigator will acquire new skills, including in utero injection techniques to study the effects of neurotrophins on cortical development in vivo, and in situ hybridization techniques that will be used to analyze the developmental expression of tyrosine kinase receptors in specific populations of cortical neurons. The overall goal of this proposal is to advance the principal investigator's capabilities as a neuroscientist, clinician and teacher, so that she will be able to contribute effectively to the understanding of neocortical development. This understanding will ultimately advance the prevention and treatment of conditions such as mental retardation, learning disabilities and epilepsy, which are often due to underlying migrational defects, disorders of lamination and other aberrations of cortical development.
| Brunstrom, J E (2001) Clinical considerations in cerebral palsy and spasticity. J Child Neurol 16:10-5 |
