Oligodendrocytes and the myelin sheaths that they produce are vulnerable to a variety of diseases and injuries, including multiple sclerosis (MS), undernutrition and ischemic insults. Prevention of oligodendrocyte death and promotion of remyelination are crucial to recovery. The object of this application is to determine the mechanisms by which insulin-like growth factor 1(IGF-1) protects cells of the oligodendrocyte lineage and myelin from damage and stimulates their recovery from injury. The investigator hypothesizes that IGF-1 protects oligodendrocytes and myelin from injury and promotes remyelination following injury. Furthermore, the investigator proposes that IGF-1 acts directly on cells of the oligodendrocyte lineage through mechanisms mediated by the type-1 IGF-1 receptor (IGFIR) and involving both inhibition of apoptosis signals and stimulation of growth and survival pathways. The applicant's hypotheses are supported by: (1) findings that demyelinating insults induce brain IGF-1 gene expression in a fashion temporospatially related to the injury; (2) the data showing that IGF-1 overexpressing transgenic mice exhibit marked increases in myelin and myelin-specific protein mRNA abundance as well as a significant increase in oligodendrocyte number; and (3) studies showing that IGF-1 protects cultured oligodendrocytes and myelin from the damage induced by tumor necrosis factor (TNF-alpha), a cytokine implicated in MS and other demyelinating disorders. To further understand IGF-1's actions and its mechanisms in protecting oligodendrocytes and myelin from damage the investigator proposes to: 1) determine the signaling pathways that mediate IGF-1's actions in protecting oligodendrocytes and myelin from injury caused by TNF-alpha 2) confirm that IGF-1 protects against TNF-alpha-induced oligodendrocyte and myelin injury in vivo by cross-breeding IGF-1transgenic mice to TNF-alpha transgenic mice and then evaluating oligodendrocyte survival and function; (3) determine IGF-1's actions on the oligodendrocytes and myelin recovery following injury by generating transgenic mice that conditionally express IGF-1 and evaluating the effects of induced IGF-1 overexpression on the oligodendrocyte lineage and myelin after injury; and (4) determine whether IGF-1 actions on oligodendrocytes and myelin are direct by studying mutant mice in whom IGF-IR expression is specifically ablated in oligodendrocytes.
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