Neuroinflammation is a prominent feature of the CNS response to acute injury, infection, and chronic neurodegeneration, and represents a potential target for treating CNS disorders, including Alzheimer's disease (AD). Elaboration of inflammatory responses depends on key molecular players that drive interactions among cells. One of these players is IL-1beta, a proinflammatory cytokine implicated in acute CNS inflammation and AD. Information has been gained about the potential roles of IL-1beta and related members of the IL-1 ligand/receptor family in acute CNS injury paradigms and some chronic disease models, using short-term infusion and viral delivery as well as genetic knockout systems. However, the short-term infusion and viral delivery systems do not provide chronic stimuli and the genetic knockout systems are complicated by potential compensatory changes during development. To overcome these issues, we propose in this R21 application to engineer two lines of transgenic mice that harbor transcriptionally silent transgenes for IL-1beta and its native antagonist, IL-1ra, respectively. Using a viral vector expressing cre recombinase, sustained expression of the transgene can be initiated at a selected age and in a specific region of brain. This somatic mosaic technology thus provides a method to conditionally and regionally secrete IL-1beta or IL-1ra within brain parenchyma, allowing studies of chronic elevation of these cytokines without confounding issues of compensatory changes during development.
Three aims constitute this proposal. In the first aim, vectors will be constructed and extensively tested prior to introduction into transgenic lines.
In aim 2, transgenic lines will be created and characterized for transgene activation and downstream effects in the absence of other pathology or insults.
In Aim 3 these animals will be employed to assess the effect of chronic IL-1beta and IL-1ra production on disease pathogenesis, specifically by crossing these mice with a transgenic model of Alzheimer's disease. These transgenic mouse lines will provide a powerful model to explore the contribution of IL-1 to neurodegenerative disorders and other neurological conditions such as stroke and traumatic brain injury.
