Proteins of the transmembrane immunoglobulin and mucin (TIM) family have been linked to a wide variety of functions in mice and humans. The founding member of the family, TIM-1, was first described as a receptor for the hepatitis A virus (HAVcr-1). Initial interest in the possible role of TIM-1 in immunity focused on T cells, due to an association between TIM-1 polymorphisms and commitment of helper T cells to either the Th1 or Th2 lineage. More recent studies have greatly broadened the possible role of TIM-1 in the immune system, including implicating this protein in the regulation of mast cells, which are also intimately involved in atopic disease. Our approach to understanding the function of TIM-1 has been to focus mainly on the signaling pathways downstream of this protein, as well as its cell biology. We believe that this approach is an important complement to the in vivo studies of others, which have yet to yield a consistent story regarding TIM-1 function in mouse models of atopic disease. Our recent studies have begun to reveal interesting biology associated with the function of TIM-1 in T cells. In this renewal application, we will continue our efforts to define te function of TIM-1 on T cells, but also broaden our studies to include investigation of the role of this protein in mast cells, both in vitro and in vivo. We believe that the studies outlined in this proposal have great potential to aid in the understanding of the effects of in vivo modulation of TIM-1, which has shown potential in pre-clinical models of asthma.
The last twenty-five years have seen a significant increase in the incidence of asthma in developed nations, prompting widespread interest in the causes for this increase. Genetic studies have implicated differences in the protein TIM-1 (transmembrane immunoglobulin and mucin domain-1) as contributing to relative susceptibility to allergic asthma in both mice and humans. However, the mechanistic basis for this effect is not yet known. Furthermore manipulation of TIM-1 with monoclonal antibodies has shown promise in the modulation of asthma in mouse models. Since the mechanism by which these antibodies function is not clear, it is important to define how these reagents modulate asthma, if TIM-1 is to be used as a target for human disease.
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