Fetal endotoxin exposure and regulation of amino acid supply

胎儿内毒素暴露与氨基酸供应的调节

• 批准号: 341265-2012
• 负责人: Regnault, Timothy
• 金额: $ 1.97万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=595356
• 关键词: Fetal; endotoxin; exposure; regulation; amino

Maternal dietary, environment and pathogen-induced stress during pregnancy are important factors contributing to in utero growth, survival after birth and postnatal health. In particular, pathogen-induced bacterial infections result in significant losses to agriculture. Treatment of healthy pregnant animals with bacterial cell wall components, termed lipopolysaccharide (LPS) provides an important approach for modeling how infection adversely affects pregnancy outcomes. Exposure to LPS in fetal life, results in low birth weight and animal losses. Additionally, in postnatal animals, LPS exposure affects skeletal muscle development providing a basis for reduced protein development; however how LPS infection during fetal development may impact future muscle growth capacity, have not been clearly defined. Lysine is an essential amino acid required for fetal development and growth. Perturbations to the system of lysine supply from mother to fetus and into the fetuses' developing tissue beds, (e.g., fetal muscle) adversely affect growth potential. During pregnancy, circulating levels of lysine are increased in animal fetal preparations associated with low birth weight. This suggests that there is potentially an outward movement of lysine (thereby reducing muscle development) occurring from fetal tissues during conditions associated with the development of low birth weight animals. The promotion of this movement occurs possibly through the activation of a lysine amino acid transporter component under a LPS challenge. This activation sets the scene for reduced protein development, as a result of substrate loss, together with stress induced protein building machinery inactivation in fetal life. This presents a significant problem for sustained muscle growth and development in postnatal life. Our work is aimed at understanding how infections alter fetal muscle development. The outcomes will define the molecular mechanisms regulating fetal protein dynamics following LPS treatment and thus probe the basic mechanisms underlying fetal muscle loss and or future growth potential following infection during pregnancy, which is a significant economical problem facing livestock production facilities.

孕妇在怀孕期间的饮食、环境和病原体引起的压力是影响子宫内生长、出生后存活和产后健康的重要因素。特别是，病原体引起的细菌感染给农业造成重大损失。用细菌细胞壁成分（称为脂多糖（LPS））治疗健康妊娠动物，为模拟感染对妊娠结局的不利影响提供了重要方法。胎儿期暴露于LPS会导致低出生体重和动物损失。此外，在出生后的动物中，LPS暴露会影响骨骼肌的发育，为蛋白质发育减少提供了基础；然而，胎儿发育期间的LPS感染如何影响未来的肌肉生长能力，还没有明确的定义。赖氨酸是胎儿发育和生长所必需的氨基酸。从母体到胎儿以及进入胎儿发育组织床（如胎儿肌肉）的赖氨酸供应系统受到干扰，会对生长潜力产生不利影响。在怀孕期间，与低出生体重相关的动物胎儿制剂中赖氨酸循环水平升高。这表明，在与低出生体重动物发育相关的条件下，胎儿组织中可能存在赖氨酸的向外运动（从而减少肌肉发育）。这种运动的促进可能是通过在LPS刺激下激活赖氨酸氨基酸转运体来实现的。这种激活设置了减少蛋白质发育的场景，作为底物损失的结果，以及胎儿生命中应激诱导的蛋白质构建机制失活。这对产后肌肉的持续生长和发育提出了一个重大问题。我们的工作旨在了解感染是如何改变胎儿肌肉发育的。这些结果将明确LPS处理后调节胎儿蛋白动力学的分子机制，从而探讨妊娠期感染后胎儿肌肉损失和/或未来生长潜力的基本机制，这是畜牧生产设施面临的一个重大经济问题。