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: 2114726
• 负责人: Amanda Davis
• 金额: $ 20.08万
• 依托单位: SUNY College at Cortland
• 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=2114726&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.

该合作项目研究了神经酰胺脂质在调节绵羊哺乳期葡萄糖动态中的作用，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对环境负面影响的潜在手段。营养浪费较少的绵羊和奶牛的牛奶就是一个例子，为了实现这一目标，有必要了解这些动物的哺乳期减少母体肌肉对葡萄糖的吸收和增加葡萄糖利用率的机制。乳腺的调节是出生后为支持乳汁合成而发生的生理调整，但尚不清楚这些反应是如何协调的，该项目扩展了证据表明神经酰胺可能会增加乳腺的营养供应以促进乳汁合成。将量化母羊中神经酰胺水平的增加和减少，并将在肌肉细胞培养中研究神经酰胺对肌肉的影响机制。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和新型食品的作用的了解。纽约州立大学科特兰分校的两名学生将通过本科生研究经验项目（REU）进行研究，而康奈尔大学的两名研究生将参与这项研究。研究生和教师将通过与附近的科学中心博物馆合作，学习如何向公众有效地传播科学知识，并为科学中心和纽约州博览会举办展览，向公众传授可持续动物知识。支持哺乳开始的一个基本顺势调节机制是降低骨骼肌中的胰岛素敏感性，从而节省葡萄糖用于乳汁合成，从而有助于新生儿的存活。经典研究表明，母体胰岛素抵抗是介导的。研究人员提出，这种传统观点是通过垂体生长激素（ST）和生长轴解偶联（即减少肝脏的胰岛素样生长因子-1 分泌）来实现的。顺流传递是不完全的，并且已确定神经酰胺是 ST 作用、葡萄糖分配和泌乳的潜在介质。神经酰胺导致母体胰岛素抵抗以支持哺乳动物乳汁合成的假设将被测试，以验证神经酰胺是否具有抑制作用。合成增加胰岛素敏感性以减少产奶量，以及诱导神经酰胺合成是否是降低胰岛素敏感性以维持产奶量的一种手段。此外，肌管中涉及神经酰胺的胰岛素拮抗机制也将是。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模型将被用来定义神经酰胺在哺乳动物哺乳期间的顺势作用，这可能会带来提高产奶效率的新方法。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，并被视为值得通过使用基金会的智力优点和更广泛的影响审查标准进行评估来支持。