This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tolloid-like 1 is an astacin-like metalloproteases that cleaves components of the extracellular matrix as well as the bone morphogenetic protein inhibitor, chordin. Tolloid-like 1 gene expression is regulated in a similar fashion to the process of adult neurogenesis. Ablation of Tolloid-like gene expression results in a 3-fold reduction in the level of adult neurogenesis. The Tolloid-like 1 promoter contains a potential hypoxia inducible factor element and our preliminary data suggests that this element causes an increase in Tolloid-like 1 gene expression in response to hypoxia. Interestingly, intermittent hypoxia also stimulates neurogenesis in the hippocampus of adult mice. We propose a series of experiments that will determine if Tolloid-like 1 is directly regulated by hypoxia and if this regulation is via interaction of the hypoxia inducible factor with the hypoxia response element in the Tolloid-like 1 promoter. Elucidating this mechanism will lead to a greater understanding of the regulation of adult neurogenesis.
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