Understanding biological mechanisms underlying absorption of immunoglobulins in newborn ruminants

了解新生反刍动物吸收免疫球蛋白的生物学机制

• 批准号: RGPIN-2021-02699
• 负责人: Laarman, Anne
• 金额: $ 2.4万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742165
• 关键词: Understanding; biological; mechanisms; underlying; absorption

In calves, pre-weaning morbidity and mortality remain high, at 24% and 6%, respectively. A strong predictive factor of morbidity and mortality risk is a failure to absorb immunoglobulins in colostrum. At birth, calves have no immunoglobulins, which are needed to fight off disease; until they produce their own immunoglobulins, the calf's entire adaptive immune response rests on the ability to absorb immunoglobulins fed in colostrum. Efficiency of immunoglobulin absorption is low, ranging from 25 - 50%, owing to the short time window for immunoglobulin absorption in neonatal calves. Classical research demonstrated immunoglobulin absorption to decrease rapidly in the first six hours of life. Both feeding of colostrum as well as a high bacterial load in colostrum further decrease immunoglobulin absorption, until cessation of immunoglobulin absorption at 24h of life. The cessation of immunoglobulin absorption is known as "gut closure" and was, until recently, thought to be relatively immutable at 24h of life. Recent research from our team indicates that the immunoglobulin absorption window can actually be manipulated by supplementing colostrum with butyrate. Despite the negative impact of butyrate on immunoglobulin absorption, the mere fact that the immunoglobulin absorption window can be nutritionally manipulated holds great potential to improve efficacy of immunoglobulin absorption. The objective of the proposed research is to improve our understanding of how immunoglobulin absorption is regulated in newborn calves. My hypothesis is that immunoglobulin absorption is predominantly FcRn-dependent and is regulated by cellular proliferation and establishment of epithelial barrier integrity. To test this hypothesis, the proposed research has several specific objectives: 1) Determine the role of epithelial maturation on immunoglobulin transport; 2) Investigate the role of FcRn-dependent and paracellular transport in immunoglobulin absorption; and 3)Investigate the impact of luminal bacterial load on immune response and tight junction formation. To test this hypothesis and meet the specific objectives, a series of experiments will be conducted that include in vivo and in vitro methods, and use a variety of analytical techniques from transport kinetics to microscopy to transcriptomics for a holistic approach to improving our understanding of immunoglobulin absorption in young calves. The proposed work will support one PhD, two MSc, and two undergraduate students. In all, the proposed research will improve our understanding of the regulation of immunoglobulin transport in young calves, thereby bolstering our understanding of the biological systems influencing absorption physiology of macromolecules.

在犊牛中，断奶前发病率和死亡率仍然很高，分别为 24% 和 6%。发病和死亡风险的一个强有力的预测因素是初乳中免疫球蛋白的吸收失败。小牛出生时没有抵抗疾病所需的免疫球蛋白；在它们产生自己的免疫球蛋白之前，小牛的整个适应性免疫反应都依赖于吸收初乳中喂养的免疫球蛋白的能力。由于新生犊牛免疫球蛋白吸收的时间窗口短，免疫球蛋白吸收效率较低，为25-50%。经典研究表明，免疫球蛋白的吸收在生命的前六个小时内迅速减少。初乳喂养以及初乳中的高细菌负荷都会进一步降低免疫球蛋白的吸收，直到生命 24 小时免疫球蛋白吸收停止。 免疫球蛋白吸收的停止被称为“肠道关闭”，直到最近还被认为在生命的 24 小时内相对不变。 我们团队最近的研究表明，实际上可以通过在初乳中补充丁酸盐来控制免疫球蛋白吸收窗口。尽管丁酸盐对免疫球蛋白吸收有负面影响，但可以通过营养方式控制免疫球蛋白吸收窗口这一事实本身就具有提高免疫球蛋白吸收功效的巨大潜力。拟议研究的目的是提高我们对新生牛犊免疫球蛋白吸收如何调节的理解。我的假设是免疫球蛋白吸收主要依赖于 FcRn，并受细胞增殖和上皮屏障完整性建立的调节。为了检验这一假设，拟议的研究有几个具体目标：1）确定上皮成熟对免疫球蛋白转运的作用； 2) 研究FcRn依赖性和细胞旁转运在免疫球蛋白吸收中的作用； 3）研究管腔细菌负荷对免疫反应和紧密连接形成的影响。为了检验这一假设并实现特定目标，将进行一系列实验，包括体内和体外方法，并使用从运输动力学到显微镜到转录组学的各种分析技术，以整体方法提高我们对幼牛免疫球蛋白吸收的理解。拟议的工作将支持一名博士生、两名硕士生和两名本科生。总而言之，拟议的研究将提高我们对幼牛免疫球蛋白运输调节的理解，从而增强我们对影响大分子吸收生理学的生物系统的理解。