The ultimate goals of the investigations proposed in this application is to investigate the pathogenesis of the disease process and to explore therapeutic means of genetic neurodegenerative diseases, globoid cell leukodystrophy (GLD) and Niemann-Pick disease type C (NPC), using naturally occurring murine models, twitcher and NPC mice. GLD is a genetic demyelinating disease and formed myelin degenerates as result of apoptotic death of oligodendrocytes. NPC is a neurovisceral storage disease. Preliminary studies in our laboratory indicate apoptotic death of storage neurons and abnormal myelination suggesting problems in oligodendrocytes and/or oligodendrocyte progenitor cells. Chemokines/cytokines generated by cells within the CNS apparently play significant role(s) in pathogenesis of both diseases. In the murine model of GLD, twitcher mouse, massive infiltration of hematogenous lineage cells into the CNS is noted as a natural disease process. These cellular infiltrations appear to be regulated by pro-inflammatory cytokines and their inhibitors.
In Aim 1, the mechanism of these cellular infiltration, role(s) of these hematogenous cells in the pathological process are investigated and also possible use of these cells as a vehicle to carry therapeutic gene in to the CNS will be explored.
In Aim 2, oligodendrocyte progenitor cells will be investigated in twitcher CNS during demyelination as a natural disease process and during remyelination following bone marrow transplantation. The basic genetic defect of NPC is a defective intracellular transport of cholesterol. Cholesterol is an important lipid in normal neuronal maturation and myelination. Thus, in Aim 3, the underlying mechanism(s) of abnormal myelination and developmental pathological process will be investigated in NPC mouse. In NPC in humans as well as in mouse, neuronal storage is a very conspicuous pathology. Neuronal storage materials are thought to be largely glycolipid, ganglioside GM2. In the preliminary study, cholesterol accumulation has been demonstrated in neurons. So far defective transport of exogenous cholesterol has been demonstrated only in cultured NPC fibroblasts. We hypothesize that similar defect can be detected in neurons and in Aim 4, the hypothesis will be tested using cerebellar and/or hippocampal slice culture. Neurons in NPC die of apoptosis. Our preliminary studies have shown increasing expression of TNF-alphamRNA and intracellular proteins associated with death domain were upregulated, suggesting significant role of TNF-alpha in apoptotic neurodegeneration. Recent studies indicate that TNF-alpha promotes neurodegeneration through inhibition of survival signals activated by insulin-like growth factor receptor. Therefore, in Aim 5 possible protective role of insulin-like growth factor for neuronal degeneration will be tested by interbreeding NPC mouse with IGF-I transgenic mouse.
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