Dr. David Dallas Awarded Prestigious NIH Pathway to Independence Award

david

The National Institute of Health (NIH) Pathway to Independence Award counteracts a problematic statistic: the average age for an investigator to receive a major NIH grant is 43. The NIH’s K99/R00 award is aimed to support younger scientists in their transition from post-doctoral fellows to independent scientists with governmental support. Only a few awards are given each year and only exceptional research programs are funded. The initial mentored phase (K99) provides a salary and funding for two years. Fellows then transition into faculty positions and the R00 phase, which is the equivalent of a full R01 grant.

Dr. Dallas graduated with a B.A. in Health Sciences from Rice University in 2008. He completed his Ph.D. at UC Davis in 2012 in Nutritional Biology under the mentorship of the Foods for Health Institute faculty Drs. Bruce German, Carlito Lebrilla and Mark Underwood. Dr. Dallas then transitioned to a post-doctoral fellowship funded by the USDA Agriculture and Food Research Institute in UC Davis Department of Food Science & Technology, and the Foods for Health Institute. In both his Ph.D. and post-doctoral fellowship, Dr. Dallas’s research focuses on how to improve premature infant nourishment by examining how milk proteins are digested both within the mammary gland and the infant gut.

Each year, over half a million infants are born prematurely in the United States. Although most of these infants now survive due to the immense advances in medicine, they are at high risk for a variety of conditions, including necrotizing enterocolitis, learning and behavioral problems, metabolic bone syndrome, chronic lung disease, and cerebral palsy. Preterm infants require more protein per kilogram of body weight than normal term infants to ensure proper growth and development. Traditionally, milk protein was considered a simple source of amino acids for protein synthesis in order to meet that need, but there are hundreds of unique proteins found in milk. Many of these milk proteins, despite much research, have not been ascribed functions.

Dr. Dallas hypothesized that many milk proteins serve as a source for encrypted bioactive peptides that are only released during infant digestion, which ignited Dr. Dallas’s mission to discover the functions of milk peptides in the developing infant. The K99/R00 grant proposal will test several hypotheses related to his research: first, that milk disassembles its proteins within the mammary glands and in the infant’s GI tract. Second, that proteolysis within the mammary gland and in the infant is carried out by specific proteases; and proteins are degraded into specific functional peptides. Third, certain milk peptides will have pathogenic-specific antimicrobial action, commensal-specific prebiotic action, and immunodulatory actions.

To begin his research, Dr. Dallas asked Dr. Mark Underwood, head of the Neonatal Intensive Care Unit in the UC Davis Medical School, if it would be possible to obtain gastric samples from term and preterm infants. Dr. Mark Underwood realized that samples could be obtained from infants that were fed via oro-or naso gastric tubing, and provided the sample collection needed for the research. Dr. Dallas then collaborated with Dr. Carlito Lebrilla and his post-doctoral fellow, Dr. Andres Guerrero, and together they developed a state-of-the-art analytical mass spectrometry platform to identify the released peptides. With this technology, they identified over 500 novel naturally-occurring peptides in human milk – nearly five times the number of peptides identified in previous research.

This data supports Dr. Dallas’s first hypothesis by demonstrating that milk proteins are partially pre-digested within the mammary gland by the mother’s own proteases. Dr. Dallas then collaborated with Dr. Nora Khaldi to evaluate which enzymes played a role in the degradation of the milk proteins, revealing that degradation was due to milk proteases including plasmin (the enzyme responsible for clot formation in the blood), cathepsin D, and elastase. Dr. Dallas investigated the functions of these peptides with Dr. Charles Bevins and Patricia Castillo, designing assays to show that the pool of human milk peptides can inhibit the growth of infant-related pathogens such as Escherichia coli and Staphylococcus aureus.

The team then evaluated what happens to the milk in the infant’s stomach. Dr. Dallas compared the amount of protein digestion in the mammary gland and in the infant’s stomach, and found that free peptides are 3.5 fold greater in the stomach. Previous studies have led scientists to believe that protein digestion did not occur in the stomach because the infant’s pH was too high.  However, Dr. Dallas’s work shows the enzymes secreted in mother’s milk continue to function in the infant’s stomach, and protein cleavage is very specific. Several peptides from key proteins (serum albumin, lactoferrin, α-lactalbumin and bile salt activated lipase) were not found in the intact milk, but in the infant’s stomach. These peptides were matched to known functional peptides specifically having antimicrobial, immunomodulatory, and calcium binding properties. The milk proteins are digested, and the released peptides serve in functional roles in the gut; interacting with bacteria and the immune system. This shows that the mother continues to control digestion even within her infant’s stomach.

Dr. Dallas’s research shows that the mother provides the essential enzymes needed for protein digestion initiation, and that protein cleavage is a controlled process in the mammary gland and infant’s stomach. Preterm infants may lack the proper enzymes to produce these antimicrobial, immunomodulatory and calcium-binding functional peptides, possibly leading to improper growth, susceptibility to sepsis, necrotizing enterocolitis, and metabolic bone disease. Dr. Dallas is now investigating why premature babies are not obtaining those vital nutrients and how premature mother’s milk compares with mature milk. Ultimately, Dr. Dallas’s research in milk proteins is finding ways to improve infant nourishment, developing a better understanding of human digestion, and identifying novel functional molecules.