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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Career Transition Award (K99)
Project #
1K99HD079561-01
Application #
8678181
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Raiten, Daniel J
Project Start
2014-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$78,689
Indirect Cost
$5,829
Name
University of California Davis
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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:
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
Nielsen, Søren Drud; Beverly, Robert L; Qu, Yunyao et al. (2017) Milk bioactive peptide database: A comprehensive database of milk protein-derived bioactive peptides and novel visualization. Food Chem 232:673-682
Dallas, David C; Citerne, Florine; Tian, Tian et al. (2016) Peptidomic analysis reveals proteolytic activity of kefir microorganisms on bovine milk proteins. Food Chem 197:273-84
Picariello, Gianluca; Addeo, Francesco; Ferranti, Pasquale et al. (2016) Antibody-independent identification of bovine milk-derived peptides in breast-milk. Food Funct 7:3402-9
Dallas, David C; Guerrero, Andres; Parker, Evan A et al. (2015) Current peptidomics: applications, purification, identification, quantification, and functional analysis. Proteomics 15:1026-38
Dallas, David C; Smink, Christina J; Robinson, Randall C et al. (2015) Endogenous human milk peptide release is greater after preterm birth than term birth. J Nutr 145:425-33
Dallas, David C; Murray, Niamh M; Gan, Junai (2015) Proteolytic Systems in Milk: Perspectives on the Evolutionary Function within the Mammary Gland and the Infant. J Mammary Gland Biol Neoplasia 20:133-47
Guerrero, Andres; Dallas, David C; Contreras, Stephanie et al. (2014) Mechanistic peptidomics: factors that dictate specificity in the formation of endogenous peptides in human milk. Mol Cell Proteomics 13:3343-51

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