Every year, nearly 800,000 people in the United States suffer a stroke, a major cause of mortality and the leading preventable cause of disability. Most of these incidents are first-time strokes, and nearly 9 out of 10 strokes can be classified as ischemic in etiology. Such strokes occur when a clot or a mass blocks an artery supplying part of the brain, cutting off blood flow and often leading to permanent neuronal injury. Microglia are brain-resident cells of the macrophage lineage that activate rapidly in response to a variety of stimuli and injuries, including ischemic stroke. Upon activation, microglia undergo morphological changes, increase expression of markers including CD68 and major histocompatibility complex class II, and produce pro-inflammatory cytokines such as tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6). Activated microglia are commonly observed in many brain diseases in addition to stroke, including Alzheimer's and Parkinson's diseases, and are regarded as key mediators of neuro- inflammation. How microglial activation affects brain injury is complex, since they can mediate both beneficial and detrimental effects, protecting neurons by removing apoptotic cells and debris via phagocytic processes, or potentially contributing to injury through their pro-inflammatory activities. Allograft inflammatory factor-1 (AIF1, also known as Iba1) is a highly conserved 17kD Ca2+ binding protein expressed in microglia and upregulated in response to neural injury. While AIF1/Iba1 is widely used as a marker of microglia, its specific contributions to microglia homeostasis and activation are not well understood. We have generated both global and conditional alleles to inactivate AIF1/Iba1 expression in mice; preliminary studies suggest notably larger areas of stroke injury in mice lacking AIF1/Iba1. In this proposal, we will use loss of function studies to assess the in vivo contribution of AIF1/Iba1 to basic microglial functions, such as migration and phagocytosis, which are important for response to neural injury. We will also determine how loss of AIF1/Iba1 affects the integrated in vivo response in a mouse model of ischemic stroke. These studies will add to our understanding of microglial function in stroke recovery, and characterize how AIF1/Iba1 contributes to recovery in this setting.
Stroke is a major cause of mortality and the leading preventable cause of disability in the U.S; most strokes result from a clot that blocks off an artery and interrupts blood flow to a part of the brain, depriving that tissue of oxygen and nutrients to the point where irreversible cell damage occurs. Part of the body's response to stroke includes activation of inflammatory cells in the brain, but this activation may have both helpful and harmful effects. This proposal seeks to improve understanding of these inflammatory cells by studying a key molecule, AIF1/Iba1, which is turned on in these cells in response to stroke. Better understanding of AIF1/Iba1 function in brain injury response may lead to new methods for prevention or treatment of stroke and associated disability.
