Many neurodevelopmental deficits (i.e., cerebral palsy, epilepsy, mental retardation) are the consequences of prenatal insults or injuries to the brain, which often extend into adulthood, causing significant burden to affected patients, families, and society. Brain development, the underlying basis of mental competency, has been studied mainly by focusing on the neuronal components necessary for lamination and connectivity. Unfortunately, much less attention has been paid to development of glial cell populations, which are most affected in perinatal injury and serve as an important reservoir of neural stem cells throughout life. The unifying focus of this program project application is the use of pre- and peri-natal injury models to better define the role of cells of the glial lineage in disease progression from three interrelated directions: the role of the extracellular milieu proteoglycan components in glial specification and migration;the role of TNF-a/IGF-1 signaling in oligodendrocyte recovery from ischemia in vitro and in vivo;and the study of a naturally occurring injury model, Batten disease. Project I focuses on the dynamic interplay of ECM components, especially aggrecan, and gliogenesis during normal brain development and remodeling of the ECM in a prenatal brain trauma model. Project II addresses TNF-a/IGF-1 signaling in prenatal brain ischemia which causes oligodendrocyte injury and subsequent myelin recovery by increased neural activity. Project IV is aimed toward understanding the pathogenesis of Batten disease, and developing chemical chaperone therapy for patients with certain forms of this disorder and other neurodegenerative diseases due to misfolded proteins. A comprehensive multidisciplinary approach using biochemical, molecular, genetic, morphologic, and cell- and slice-culture techniques will be used in all three projects. There is overall emphasis on embryonic injury modalities, molecular expression analysis, and signaling paradigms to gain an understanding of normal and interrupted embryonic brain development. A core service will support administrative functions as well as shared equipment, supplies, technical facilities, and expertise for tissue culture and microscopy.
Cerebral palsy, epilepsy, and behavioral as well as cognitive deficits are common outcomes of prenatal insults or injuries during critical periods of prenatal development, or of genetic disorders manifested during fetal life. The combined effort of the three projects that constitute this program is designed to address the underlying etiology of these prenatal abnormalities, perhaps leading to therapeutic strategies.
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