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.

这个合作项目调查神经酰胺脂类在调节绵羊哺乳期间的血糖动态中的作用。提高农场动物的养分利用效率是提高全球粮食安全和减少对环境的负面影响的潜在手段。用更少的营养废物提高羊和牛生产营养密集型牛奶的效率就是一个例子。为了实现这一目标，有必要了解这些动物的哺乳机制。母体肌肉对胰岛素刺激的葡萄糖摄取减少，乳腺对葡萄糖的利用增加，这些都是出生后发生的支持乳汁合成的生理调节，但尚不清楚这些反应是如何协调的。该项目的扩展依据是有证据表明神经酰胺可以增加乳汁合成所需的乳腺营养供应。神经酰胺水平的增加和降低对绵羊的影响将被量化，神经酰胺对肌肉的作用机制将在肌肉细胞培养中进行研究。研究将被整合到一个教育和推广计划中，重点是提高公众对食用动物生产的理解，以及新策略(如生物技术)在增加牛奶合成方面的作用。纽约州立大学考特兰分校每年有两名学生通过本科生研究体验(REU)项目进行研究，康奈尔大学的两名研究生将参与研究。REU和研究生以及教职员工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。将为科学中心和纽约州大博览会开发一个展览，向公众介绍可持续的动物农业。一个支持哺乳开始的基本顺势机制是降低骨骼肌中的胰岛素敏感性，这将节省葡萄糖用于乳房合成牛奶，有助于新生儿的存活。经典研究推测，母亲的胰岛素抵抗是由垂体促生长激素(ST)和促生长轴的解偶联(即肝脏分泌的胰岛素样生长因子-1减少)介导的。研究人员提出，这种传统的顺势疗法观点是不完整的，并已确定神经酰胺是ST作用、葡萄糖分配和哺乳的潜在媒介。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得到验证。整个动物研究将确定抑制神经酰胺合成是否会增加胰岛素敏感性从而减少产奶量，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一种手段。此外，还将描述涉及神经酰胺在肌管中的胰岛素拮抗机制。利用脂类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，将被用来确定神经酰胺在哺乳动物哺乳期间的顺势作用。结果可能会带来提高牛奶生产效率的新方法，这将使相关的农业行业受益。本科生和研究生将参与研究项目，动物科学传播课程的本科生将生成针对普通公众的播客。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。