Apolipopoprotein E (apoE) is a 299 amino acid protein with multiple biological properties, including a role in cholesterol trafficking, immumomodulation, and a putative role in nerve injury and repair. Recent evidence suggests that the one of the three common apoE isoforms, E4 is associated with increased risk for developing Alzheimer's disease (sporadic and late onset familial), and poor prognosis after a variety of acute neurological insults, including closed head injury, intracranial, hemorrhage, and cerebral ischemia. We will test the hypothesis that apoE is a biologically relevant mediator of the CNS response to acute and chronic injury. We will also test the hypothesis that there are isoform-specific differences in these immunoregulatory functions. Our preliminary evidence suggests that apoE suppresses the endogenous inflammatory response mediated by glial cells, and may also inhibit the cellular immune response when the blood-brain barrier is compromised. We have also demonstrated that apoE modulates the CNS reaction to focal ischemia in vivo, and our preliminary observations are consistent with the possibility that these effects are isoform-specific. We propose to characterize the role of apoE in modulating the CNS inflammatory response by utilizing apoE deficient mice and mice expressing the human E2, E3, and E4 transgenes to prepare cell culture models and in vivo models of CNS injury and inflammation. This supervised research experience will be integrated with advanced didactic coursework in immunology and neurobiology. In the latter part of the grant period, we will examine the molecular basis by which apoE affects the immune response. Specifically, we will focus on receptor interactions and modulation of signal transduction pathways. During this period, the focus will be on developing more sophisticated research skill to facilitate independence. In summary, this proposal will examine the role of apoE in modulating the CNS immune response and will provide the fundamental training in immunology and neurobiology necessary for developing and independent research career in neuroimmunology.