Deciphering the function of naturally occurring peptides in human milk

描述(申请人提供)：多肽构成了人体内的大多数信号系统。这些在肠道、大脑、胰腺、皮肤和其他器官中产生的多肽具有深远的影响--例如控制食物的摄入、新陈代谢、血压、行为、排卵和昼夜节律。在许多情况下，这些信号肽的共同模式可以追溯到数亿年的进化过程中。然而，多肽作为治疗信号载体的应用还没有得到充分的探索。我们已经证明，通过新的基于质谱学的肽组学方法，超过500个肽是在乳汁中产生的，在乳腺本身。这些自然产生的多肽代表了一类新的食物分子，它们在母亲和婴儿体内具有尚未确定的信号功能。我们已经证明，超过10%的多肽与已知的具有抗菌和免疫调节功能的多肽同源。其余的还没有发现功能。第一代测试发现，所鉴定的多肽具有抗菌作用--作为一个整体，这些多肽抑制了几种致病菌的生长。拟议的研究计划将定义天然乳多肽的整个范围，它们的不同功能，以及哪些特定序列是相关的。将检查多肽的特定生物相关作用，包括抗菌、抗真菌、益生菌、抗寄生虫和抗炎作用。研究牛奶中的多肽将揭示可应用于婴儿和成人健康的动态和复杂的大分子系统。我的长期目标是利用营养学或食品科学终身教职在一流研究型大学的教职，建立一个在人类健康方面具有高度影响力的研究项目。我相信，这项研究计划的核心将旨在了解母乳对婴儿健康的影响，特别是从消化的角度，并利用这种理解来指导所有年龄段的营养和健康。加州大学戴维斯分校是在K99奖项阶段实现这一提案目标的首要地点。我在博士和博士后第一年的工作中结识的合作者使这个项目成为可能。加州大学戴维斯分校不仅在Lebrilla博士和Barile博士的实验室提供最先进的分析质谱学，还能够通过与加州大学戴维斯医学院新生儿重症监护病房主任Mark Underwood博士合作从婴儿的胃中获取样本。此外，我还与大量的合作伙伴建立了网络，以测试奶肽在检测中的各种功能。

DESCRIPTION (provided by applicant): Peptides form the majority of signaling systems in humans. These peptides, produced in the gut, brain, pancreas, skin and other organs have far-reaching effects-controlling food intake, metabolism, blood pressure, behavior, ovulation, and circadian rhythms as examples. These signaling peptides have, in many cases, common modalities traceable back hundreds of millions of years in evolution. However, the application of peptides as therapeutic signaling agents has not been fully explored. We have shown, through novel mass spectrometry-based peptidomics methodology, that over 500 peptides are produced in human milk within the mammary gland itself. These naturally occurring peptides represent a new class of food molecules that have as yet uncharacterized signaling functions within the mother and the infant. We have shown that over 10% are homologous to known peptides with antimicrobial and immunomodulatory functions. The rest have yet to be discovered functions. First generation assays have discovered that the peptides identified have antimicrobial actions-as an ensemble, these peptides inhibited the growth of several strains of pathogenic bacteria. The proposed research program will define the entire range of naturally occurring milk peptides, their diverse functions and also which specific sequences are responsible. Peptides will be examined for specific biological- context-relevant actions, including antimicrobial, antifungal, prebiotic, anti-parasitic and anti-inflammatory actions. Investigating milk's peptides will unlock dynamic and complex system of macromolecules that can be applied to infant and adult health. My long-term goal is to leverage a Nutrition or Food Science tenure-track faculty position at a tier-one research university to establish a high-impact research program in human health. I am convinced that the core of this research program will be designed to understand the effects of human milk on infant health, particularly from the perspective of digestion, and use this understanding to guide the nourishment and health of all ages. University of California, Davis, is the premier place to accomplish the aims of this proposal during the K99 phase of the award. The collaborators I have brought together during my Ph.D. and first year of post- doctoral work have made this project possible. UC Davis provides not only state-of-the-art analytical mass spectrometry in Dr. Lebrilla's and Dr. Barile's labs, but also the ability to obtain samples from te stomachs of infants through a collaboration with Dr. Mark Underwood, the head of the neonatal intensive care unit at the UC Davis Medical School. In addition, I have networked with a large number of collaborators to test the milk peptides for a variety of functions in assays.