Collaborative Research: Revisiting the homeorhetic mechanisms of lactation: The role of ceramide

合作研究：重新审视哺乳的顺势机制：神经酰胺的作用

• 批准号: 2114725
• 负责人: Joseph McFadden
• 金额: $ 102.16万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2114725&HistoricalAwards=false
• 关键词: Collaborative; Research; Revisiting; homeorhetic; mechanisms

This collaborative project investigates the role of ceramide lipids in regulating glucose dynamics during lactation in sheep. Increasing the efficiency of nutrient use in farm animals is a potential means to increase global food security and reduce negative environmental impact. Increasing the efficiency to produce nutrient-dense milk from sheep and cows with less nutrient waste is one example. To achieve this goal, it is necessary to understand the mechanisms of lactation in these animals. Reduced insulin-stimulated uptake of glucose by maternal muscle and increased glucose utilization by the mammary gland are physiological adjustments that occur after birth to support milk synthesis, but it is not clear how these responses are coordinated. This project expands upon evidence suggesting that ceramide may increase nutrient supply to the mammary gland for milk synthesis. The effects of increasing and decreasing ceramide levels will be quantified in ewes, and mechanisms of ceramide’s effects on muscle will be studied in muscle cell culture. Research will be integrated within an education and outreach program focused on improving public understanding of food animal production and the role of novel strategies (e.g., biotechnology) in increasing milk synthesis. Two students per year from the State University of New York at Cortland will conduct research through the Research Experiences for Undergraduates (REU) program, and two Cornell graduate students will contribute to the research. The REU and graduate students, along with faculty, will learn how to communicate science to the public effectively through a collaboration with the nearby Sciencenter museum. An exhibit for the Sciencenter and the Great New York State Fair will be developed to teach the public about sustainable animal agriculture.A fundamental homeorhetic mechanism that develops to support the onset of lactation is the reduction of insulin sensitivity in skeletal muscle, which spares glucose for the mammary synthesis of milk, contributing to survival of the neonate. Classic studies infer that maternal insulin resistance is mediated by pituitary somatotropin (ST) and uncoupling of the somatotropic axis (i.e., reduced insulin-like growth factor-1 secretion from liver). The researchers propose that this traditional view of homeorhesis is incomplete, and have identified ceramide as a potential mediator of ST action, glucose partitioning, and lactation. The hypothesis that ceramide causes maternal insulin resistance to support milk synthesis in mammals will be tested. Whole animal studies will establish whether the inhibition of ceramide synthesis increases insulin sensitivity to decrease milk production, and whether the induction of ceramide synthesis is a means to decrease insulin sensitivity to sustain milk production. In addition, the mechanisms of insulin antagonism that involve ceramide in myotubes will be delineated. Experience utilizing lipidomics and studying insulin kinetics, as well as a justified Ovis aries (sheep) model, will be leveraged to define the homeorhetic role of ceramide during mammalian lactation. Results may lead to new ways to increase milk production efficiency, which would benefit the associated agricultural industries. Undergraduate and graduate students will participate in the research project, and undergraduates in an animal science communications course will generate podcasts targeted to the general public.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

本合作项目研究神经酰胺脂质在绵羊泌乳期间调节葡萄糖动力学中的作用。提高农场动物的营养利用效率是提高全球粮食安全和减少负面环境影响的潜在手段。例如，提高绵羊和奶牛生产营养丰富的牛奶的效率，减少营养浪费就是一个例子。为了实现这一目标，有必要了解这些动物的泌乳机制。母体肌肉对胰岛素刺激的葡萄糖摄取减少和乳腺对葡萄糖的利用增加是出生后发生的生理调节，以支持乳汁合成，但尚不清楚这些反应如何协调。该项目扩大了证据表明，神经酰胺可能会增加营养供应到乳腺牛奶合成。增加和减少神经酰胺水平的影响将在母羊中进行量化，神经酰胺对肌肉的影响机制将在肌肉细胞培养中进行研究。研究将纳入教育和推广计划，重点是提高公众对食用动物生产的理解和新战略的作用（例如，生物技术）增加牛奶合成。每年有两名来自科特兰纽约州立大学的学生将通过本科生研究经验（REU）计划进行研究，两名康奈尔大学的研究生将为研究做出贡献。REU和研究生，沿着教师，将学习如何通过与附近的科学中心博物馆合作，有效地向公众传播科学。将为科学中心和大纽约州博览会举办一个展览，向公众介绍可持续的畜牧业。一个基本的顺势疗法机制，发展到支持哺乳期的开始是骨骼肌胰岛素敏感性的降低，这为乳房合成乳汁节省了葡萄糖，有助于新生儿的生存。经典研究推断母体胰岛素抵抗是由垂体促生长素（ST）和促生长轴的解偶联（即，减少胰岛素样生长因子-1从肝脏的分泌）。研究人员提出，这种传统的顺势作用观点是不完整的，并已确定神经酰胺作为ST作用，葡萄糖分配和泌乳的潜在介质。神经酰胺引起母体胰岛素抵抗以支持哺乳动物乳汁合成的假设将被检验。全动物研究将确定神经酰胺合成的抑制是否增加胰岛素敏感性以减少产奶量，以及神经酰胺合成的诱导是否是降低胰岛素敏感性以维持产奶量的手段。此外，胰岛素拮抗机制，涉及神经酰胺在肌管将被描绘。利用脂质组学和研究胰岛素动力学的经验，以及合理的绵羊（绵羊）模型，将被用来定义哺乳动物哺乳期间神经酰胺的同源异型作用。研究结果可能会导致新的方法来提高牛奶生产效率，这将有利于相关的农业产业。本科生和研究生将参与该研究项目，动物科学传播课程的本科生将制作面向公众的播客。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。