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首页> 外文学位 >Lactation performance and milk composition studies in transgenic goats expressing recombinant proteins in the milk.
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Lactation performance and milk composition studies in transgenic goats expressing recombinant proteins in the milk.

机译：在表达牛奶中重组蛋白的转基因山羊中的泌乳性能和牛奶组成研究。

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摘要

Milk expression of recombinant proteins of pharmaceutical value in transgenic dairy animals is an emerging solution for molecules that cannot be made efficiently using the standard bioreactor platform. However, the expression of large quantities of recombinant proteins in the mammary gland can result in phenotypes with compromised lactation physiology. These negative consequences have been vaguely described in the literature and, in most cases they have not been studied in depth with view to understanding the mechanisms of mammary disruption by transgene expression. Therefore, using a transgenic herd of goats expressing recombinant human butyrylcholinesterase, the main goals of this research were to: (a) study the lactation performance and basic milk parameters (b) assess milk composition (c) explore the integrity of epithelial tight junctions, endoplasmic reticulum stress and accelerated cell death (d) investigate delayed lactogenesis and (e) assess the effects of "compensatory treatments" on transgenic lactation performance.Our findings showed that transgenic lactations were characterized by a slow/delayed start of milk production, a relatively normal milk volume at peak and a premature shutdown of milk production compared to controls. These compromised productivities were associated with a disrupted lipid secretion at the level of the secretory epithelium, and a dramatic raise in the presence of phagocytes in milk that was not associated with mammary infection. Milk composition studies indicated that transgenic goats produce lower quantities of caseins and short chain fatty acids. Through determination of serum album presence and Na:K ratio in milk we established the development of permeable tight junctions as an apparent mechanism of lactation disruption in the transgenic animals. Delayed expression of alpha-lactalbumin was proposed as a major determinant of the delayed lactogenesis observed in the transgenic goats. Immunohistochemistry studies revealed increased expression of ER-stress signalling molecules (ATF6 and Caspase 12) in transgenic goats. Finally, prepartum mammary priming as well as mammary stem cell stimulators were successfully applied to enhance milk production in transgenic goats. In conclusion, several mechanisms of mammary disruption in transgenic goats were established and this knowledge was applied to the development of treatments that can successfully improve productivity and recombinant protein output in transgenic goats.
机译：转基因奶牛动物中具有药用价值的重组蛋白的乳汁表达是无法使用标准生物反应器平台高效制备的分子的新兴解决方案。但是，在乳腺中大量重组蛋白的表达会导致泌乳生理功能受损的表型。这些负面后果已在文献中模糊地描述，并且在大多数情况下，尚未深入研究它们以了解转基因表达对乳腺破坏的机制。因此，使用表达重组人丁酰胆碱酯酶的转基因山羊，该研究的主要目标是：（a）研究泌乳性能和基本牛奶参数（b）评估牛奶成分（c）探索上皮紧密连接的完整性，内质网应激和细胞死亡加速（d）研究延迟的乳汁生成和（e）评估“补偿性治疗”对转基因泌乳性能的影响。我们的研究结果表明，转基因哺乳的特征是产奶开始缓慢/延迟，相对而言与对照组相比，高峰时的正常牛奶量和过早停产牛奶。这些生产率下降与分泌上皮水平的脂类分泌中断有关，并且在牛奶中吞噬细胞的存在下与乳腺感染无关的急剧增加。牛奶成分研究表明，转基因山羊产生较少量的酪蛋白和短链脂肪酸。通过确定牛奶中血清相册的存在和Na：K的比例，我们建立了可渗透紧密连接的发展，将其作为转基因动物泌乳破坏的明显机制。有人提出α-乳清蛋白的延迟表达是转基因山羊中观察到的延迟泌乳的主要决定因素。免疫组织化学研究表明，转基因山羊中ER应激信号分子（ATF6和Caspase 12）的表达增加。最后，成功地使用了产前乳腺刺激剂和乳腺干细胞刺激剂来提高转基因山羊的产奶量。总之，建立了转基因山羊乳腺破坏的几种机制，并将这一知识应用于可以成功提高转基因山羊生产力和重组蛋白产量的治疗方法。

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  • 作者

    Baldassarre, Hernan.;

  • 作者单位

    McGill University (Canada).;

  • 授予单位 McGill University (Canada).;
  • 学科 Agriculture Animal Culture and Nutrition.Biology Physiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 235 p.
  • 总页数 235
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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