Prerinatal injury is a significant cause of morbidity and mortality, often with long term cognative sequelae. Increasingly, different forms of injury inflicted during highly susceptible periods of development produce similar phenotypes involving behavioral and cognitive deficits and mental retardation. Importantly, the susceptibility period for the most common forms of developmental brain injuries coincides with oligodendrocyte and astrocyte differentiation and maturation. Project 1 focuses on the role of the extracellular milieu in promoting specification and migration of cells of the glial lineage during normal central nervous system (CNS) development and after traumatic embryonic brain injury. Future studies are informed by several recent findings: the demonstration of a role for aggrecan in gliogenesis;establishment of a hindbrain organotypic culture system which faithfully recapitulates the native in vivo cytoarchitecture and cell environment;and development of an acute embryonic injury model enabling the study of the protective or inhibitory role of the matrix following embryonic injury.
Two aims are proposed:
Aim 1, To analyze glial cell migration and differentiation and the importance of the extracellular milieu;
Aim 2, To elucidate the response of glial precursors to embryonic brain injury and the function of proteoglycans in this process. These studies will provide insights into mechanisms controlling astrogliogenesis and the influence of components of the glial cell precursors'environment on cell-fates, as well as elucidate how glial precursor differentiation is affected by cell-environment changes induced by trauma during brain development. Understanding the mechanisms which underlie these relationships is critical to being able to remodel the composition of the extracellular milieu, thereby influencing cell-fate during development, and devising novel therapies to foster regeneration after CNS injury.
Periventricular white matter injury (PWMI), the most frequently observed lesion in the human neonatal brain, is strongly associated with adverse outcomes such as cerebral palsy, epilepsy, behavioral and cognitive problems;however the mechanisms underlying embryonic injury neuropathology are not fully understood. Analysis of astrocyte response to injury in embryonic brain damage models will provide insight into causes of these disorders and open up new directions for therapeutic considerations.
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