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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Tolloid样1是一种astacin样金属蛋白酶，其切割细胞外基质的组分以及骨形态发生蛋白抑制剂脊索蛋白。Tolloid样1基因的表达以与成人神经发生过程相似的方式进行调节。Tolloid样基因表达的消融导致成人神经发生水平降低3倍。Tolloid样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，该元件导致Tolloid样1基因表达增加，以应对缺氧。有趣的是，间歇性缺氧也刺激成年小鼠海马体中的神经发生。我们提出了一系列的实验，将确定是否Tolloid样1是直接调节缺氧，如果这种调节是通过缺氧诱导因子与缺氧反应元件的Tolloid样1启动子的相互作用。阐明这一机制将导致更好地了解成人神经发生的调节。

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.