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.

Public Health Relevance

This project employs a novel, high-throughput, mass spectrometry-based peptide sequencing technique to identify naturally occurring milk peptides from intact milk and infant digesta samples. Milk peptides are then searched for homology with known functional peptides and then examined as an ensemble with in vitro assays for antimicrobial, probiotic and immunomodulatory function. Specific functional sequences will be determined through synthesis and fractionation approaches, and these peptides will be applied to a variety of human health applications.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Raiten, Daniel J
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Oregon State University
Schools of Public Health
United States
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Demers-Mathieu, Veronique; Qu, Yunyao; Underwood, Mark A et al. (2018) The preterm infant stomach actively degrades milk proteins with increasing breakdown across digestion time. Acta Paediatr 107:967-974
Demers-Mathieu, Veronique; Qu, Yunyao; Underwood, Mark A et al. (2018) Premature Infants have Lower Gastric Digestion Capacity for Human Milk Proteins than Term Infants. J Pediatr Gastroenterol Nutr 66:816-821
Dallas, David; Nielsen, Søren Drud (2018) Milk Peptidomics to Identify Functional Peptides and for Quality Control of Dairy Products. Methods Mol Biol 1719:223-240
Demers-Mathieu, Veronique; Underwood, Mark A; Beverly, Robert L et al. (2018) Survival of Immunoglobulins from Human Milk to Preterm Infant Gastric Samples at 1, 2, and 3 h Postprandial. Neonatology 114:242-250
Demers-Mathieu, Veronique; Nielsen, Søren Drud; Underwood, Mark A et al. (2018) Changes in Proteases, Antiproteases, and Bioactive Proteins From Mother's Breast Milk to the Premature Infant Stomach. J Pediatr Gastroenterol Nutr 66:318-324
Nielsen, Søren D; Beverly, Robert L; Dallas, David C (2017) Peptides Released from Foremilk and Hindmilk Proteins by Breast Milk Proteases Are Highly Similar. Front Nutr 4:54
Murray, Niamh M; O'Riordan, Dolores; Jacquier, Jean-Christophe et al. (2017) Validation of a paper-disk approach to facilitate the sensory evaluation of bitterness in dairy protein hydrolysates from a newly developed food-grade fractionation system. J Sens Stud 32:
Demers-Mathieu, Veronique; Nielsen, Søren Drud; Underwood, Mark A et al. (2017) Analysis of Milk from Mothers Who Delivered Prematurely Reveals Few Changes in Proteases and Protease Inhibitors across Gestational Age at Birth and Infant Postnatal Age. J Nutr 147:1152-1159
Dallas, David C; Sanctuary, Megan R; Qu, Yunyao et al. (2017) Personalizing protein nourishment. Crit Rev Food Sci Nutr 57:3313-3331
Nielsen, Søren D; Beverly, Robert L; Dallas, David C (2017) Milk Proteins Are Predigested Within the Human Mammary Gland. J Mammary Gland Biol Neoplasia 22:251-261

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