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首页> 外文学位 >Identification and characterization of Stanniocalcin-1 as a potential therapeutic protein secreted by injury-activated multipotent stromal cells.
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Identification and characterization of Stanniocalcin-1 as a potential therapeutic protein secreted by injury-activated multipotent stromal cells.

机译：斯坦诺钙素-1作为损伤激活多能基质细胞分泌的潜在治疗性蛋白质的鉴定和表征。

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摘要

Multipotent Stromal Cells (MSCs) hold great promise for future cell-based therapeutics. By understanding the mechanisms by which MSCs contribute to tissue repair, not only can insight be gained as to their potential applications, but novel therapeutic candidates can be identified as well. We determined that MSCs were activated by apoptotic cells to upregulate and secrete Stanniocalcin-1 (STC1), a highly evolutionarily-conserved mineral-regulating protein hypothesized to be stress-responsive in mammals. We determined that STC1 was required for the MSCs to elicit an anti-apoptotic effect on injured cells in two in vitro models of apoptosis. In the first model, STC1 was required but not sufficient to reduce apoptosis of fibroblasts that had been UV-irradiated. In the second model, STC1 was both required and sufficient to reduce apoptosis of ischemic lung epithelial cells. We then tested the stress-responsive nature of STC1 more directly by adopting a model of injury that allowed us to visualize calcium dynamics immediately following insult. We demonstrated that STC1 dramatically enhanced calcium wave propagation following mechanical stimulation of an epithelial monolayer. We showed that the propagation of the calcium wave was dependent on extracellular nucleotides, and that STC1 enhanced the calcium response downstream of extracellular ATP. Blocking STC1 inhibited the propagation of the calcium wave as well as the ATP-induced calcium response indicating that STC1 was required for ATP signaling. These novel data provide mechanistic grounds for the pleiotropic nature of STC1 and may have profound implications on the application of STC1 as a therapeutic target considering the ubiquity of ATP signaling in various biological processes.
机译：多功能基质细胞（MSC）对于未来基于细胞的治疗方法具有广阔的前景。通过了解MSC参与组织修复的机制，不仅可以获得关于其潜在应用的见解，而且还可以鉴定出新颖的治疗候选物。我们确定，MSC被凋亡细胞激活以上调和分泌Stanniocalcin-1（STC1），这是一种高度进化保守的矿物质调节蛋白，被认为在哺乳动物中具有应激反应性。我们确定，在两个体外凋亡模型中，MSC需要STC1才能引起对受损细胞的抗凋亡作用。在第一个模型中，STC1是必需的，但不足以减少已被紫外线照射的成纤维细胞的凋亡。在第二个模型中，既需要STC1，又要足够STC1，以减少缺血性肺上皮细胞的凋亡。然后，我们通过采用一种损伤模型使我们能够在可视化后立即查看钙动力学，从而更直接地测试了STC1的应激反应特性。我们证明STC1大大增强了机械刺激的上皮单层后钙波传播。我们表明，钙波的传播取决于细胞外核苷酸，并且STC1增强了细胞外ATP下游的钙反应。阻断STC1抑制了钙波的传播以及ATP诱导的钙反应，表明STC1是ATP信号传导所必需的。这些新颖的数据为STC1的多效性提供了机械基础，考虑到ATP信号在各种生物过程中的普遍性，可能会对STC1作为治疗靶标的应用产生深远的影响。

著录项

  • 作者

    Block, Gregory Joel.;

  • 作者单位

    Tulane University.;

  • 授予单位 Tulane University.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 144 p.
  • 总页数 144
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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