THE ROLE OF HYPOXIA IN THE REGULATION OF MAMMALIAN TOLLOID-LIKE 1

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Tolloid-like 1是一种类似阿司匹林的金属蛋白水解酶，可以分解细胞外基质的成分以及骨形态发生蛋白抑制剂Chordin。Tolloid-like 1基因表达的调控方式与成人神经发生的过程类似。去除类Tolloid基因的表达导致成人神经发生水平降低3倍。Tolloid-like 1启动子包含一个潜在的缺氧诱导因子元件，我们的初步数据表明，该元件可引起Tolloid-like 1基因在低氧条件下表达的增加。有趣的是，间歇性低氧也会刺激成年小鼠海马区的神经再生。我们提出了一系列实验，以确定Tolloid-like 1是否直接受到缺氧的调节，以及这种调节是否通过缺氧诱导因子与Tolloid-like 1启动子中的缺氧反应元件的相互作用来实现。阐明这一机制将有助于更好地理解成体神经发生的调控。

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.