The goal of this project is directed toward an understanding of the means by which abnormalities in specific extracellular macromolecules cause mental retardation and developmental defects. Absence of a specific proteoglycan (B-aggrecan) leads to abnormal neuronal cell migration and aggregation behavior in vitro and less well organized and smaller brains in certain mutant model systems. It is therefore postulated that B- aggrecan is necessary for the developmental sequelae that leads to the optimal neuron positioning and synapse formation which is required for normal neurogenesis. In order to elucidate the role of aggrecan in the processes of cell migration, adhesion and aggregation during CNS morphogenesis in normal embryonic development and in mutant systems defective in aggrecan production, the mode of association of aggrecan with neurons during the establishment of aggregates in vitro and the mechanism by which aggrecan participates in cell migration/aggregation will be determined. The timing and position of appearance of aggrecan will also be investigated and correlated with other CNS molecular markers by whole mount in situ hybridization and in situ staining of tissue sections. Expression of the aggrecan gene is cell-type specific and developmentally- dependent. It is therefore postulated that there is differentiation- associated transcriptional activation of the aggrecan gene during establishment of cortical neuron function in the CNS. In order to provide a foundation for understanding the factors and signaling pathways that may regulate transcription of the aggrecan gene during neuronal differentiation, the regulatory elements present in the aggrecan promoter will be identified; how these elements are utilized in neurons will be determined; specific DNA-binding proteins that interact with specific regions of the aggrecan promoter during neuronal differentiation will be identified; the mechanism by which putative transcription factors regulate aggrecan gene expression will be elucidated; and the effects of certain cytokines and growth factors on the regulation of the expression of aggrecan during neuronal differentiation will be examined.
| Domowicz, Miriam; Wadlington, Natasha L; Henry, Judith G et al. (2018) Glial cell responses in a murine multifactorial perinatal brain injury model. Brain Res 1681:52-63 |
| Pusic, Kae M; Pusic, Aya D; Kraig, Richard P (2016) Environmental Enrichment Stimulates Immune Cell Secretion of Exosomes that Promote CNS Myelination and May Regulate Inflammation. Cell Mol Neurobiol 36:313-325 |
| Dawson, Glyn (2016) Quantum dots and potential therapy for Krabbe's disease. J Neurosci Res 94:1293-303 |
| Walters, Ryan; Medintz, Igor L; Delehanty, James B et al. (2015) The Role of Negative Charge in the Delivery of Quantum Dots to Neurons. ASN Neuro 7: |
| Agarwal, Rishabh; Domowicz, Miriam S; Schwartz, Nancy B et al. (2015) Delivery and tracking of quantum dot peptide bioconjugates in an intact developing avian brain. ACS Chem Neurosci 6:494-504 |
| Dawson, Glyn (2015) Measuring brain lipids. Biochim Biophys Acta 1851:1026-39 |
| Pusic, Aya D; Mitchell, Heidi M; Kunkler, Phillip E et al. (2015) Spreading depression transiently disrupts myelin via interferon-gamma signaling. Exp Neurol 264:43-54 |
| Cortes, Mauricio; Cortes, Leslie K; Schwartz, Nancy B (2015) Mapping proteoglycan functions with glycosidases. Methods Mol Biol 1229:443-55 |
| Pusic, Aya D; Kraig, Richard P (2015) Phasic Treatment with Interferon Gamma Stimulates Release of Exosomes that Protect Against Spreading Depression. J Interferon Cytokine Res 35:795-807 |
| Testai, Fernando D; Xu, Hao-Liang; Kilkus, John et al. (2015) Changes in the metabolism of sphingolipids after subarachnoid hemorrhage. J Neurosci Res 93:796-805 |
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