Evaluation of recombinant bovine lactoferrin and N-linked glycan effects on infant gut health and immunity

重组牛乳铁蛋白和 N 连接聚糖对婴儿肠道健康和免疫力影响的评估

• 批准号: 10821138
• 负责人: Vanessa Patricia Dunne-Castagna
• 金额: $ 31.13万
• 依托单位: TURTLETREE LABS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10821138
• 关键词: Address; Agriculture; Animals; Anti-Inflammatory Agents; Antigens; Back; Binding; Biological; Breast Feeding; Breastfed infant; CD4 Positive T Lymphocytes; Cattle; Complex; Data; Development; Dissociation; Elements; Engineering; Ensure; Evaluation; Exclusive Breastfeeding; Fermentation; Funding; Glycoproteins; Goals; Grant; Health; Human; Human Development; Human Milk; Immune; Immunity; In Vitro; Infant; Infant Development; Infant Health; Infant formula; Inferior; Intervention; Iron; Knockout Mice; Lactoferrin; Life; Link; Lower Respiratory Tract Infection; Mannose; Marketing; Measures; Mediating; Metabolic; Methods; Milk; Milk Proteins; Modeling; Modernization; Modification; Morbidity - disease rate; Mus; Neurologic; Nutritional; Oral; Parents; Pathway interactions; Peripheral Blood Mononuclear Cell; Permeability; Phenotype; Physiological; Polysaccharides; Procedures; Process; Production; Proliferating; Protein Denaturation; Proteins; Recombinants; Recovery; Regulation; Reporting; Resources; Risk; Role; Safety; Sampling; Signal Transduction; Source; Structure; System; T-Cell Activation; Technology; Testing; United States National Institutes of Health; Work; antimicrobial; commercialization; comparative; cost; cost effective; cytokine; design; efficacy evaluation; environmental stressor; fortification; gastrointestinal infection; glycosylation; gut health; immune function; immunoregulation; improved; in vivo; infant nutrition; intestinal barrier; intestinal maturation; mannose receptor; manufacturing process; microbial; microbial host; microbiome; microbiota; monocyte; mortality; mortality risk; mouse model; nutrition; pre-clinical; prevent; pup; rRNA Genes; response; treatment group; uptake

Project Summary/Abstract Most infants currently rely on infant formula (IF) to meet their nutritional needs. However, existing infant formula is functionally inferior because it lacks breast milk bioactive proteins that are crucial to infant health and development. Consequently, formula-fed infants have increased risk of morbidity and mortality. Current technology limits the ability to add bioactive milk proteins to infant formula because manufacturing processes are resource intensive, costly, and difficult to scale. Thus, scalable technology to improve bioactive availability for fortification of infant formula is needed. Towards this goal, TurtleTree has developed precision fermentation technology to produce recombinant bovine lactoferrin (rbLf), a critical bioactive milk protein demonstrated to support gut health and immune function in infants. Not only will TurtleTree’s technology allow for inclusion of lactoferrin in all infant formulas, but the use of precision fermentation will also dissociate bioactive milk protein production from animal agriculture, as required for cow’s milk-derived lactoferrin (cMDLf), and the associated environmental stressors. In this proposal, we aim to answer two specific questions that will validate our ability to apply precision fermentation technology for infant health and commercialize rbLf as an ingredient for addition to infant formula: 1) Does the unique glycosolation profile of rbLf impact the protein’s immunomodulatory and gut function as compared to cMDLf? 2) Does rbLf improve gut health in an infant preclinical mouse model? Preliminary data supporting this proposal demonstrates the N-linked glycan profile is the only substantially unique structural element of rbLf, characterized by dominance of high-mannose type glycans (~99%) compared to cMDLf (~45%). Thus, we reason a proper evaluation of rbLf requires focused studies on physiological systems sensitive to glycan alterations, notably immune interactions (Aim 1) and gut development (Aim 2). Comparative results between differentially glycosylated lactoferrin treatment groups will distinguish glycan effects. In Aim 1, we will assess the role of lactoferrin N-linked glycosylation on immunomodulation mediated by the mannose receptor in order to understand glycan effect. In Aim 2, we will execute an intervention of orally-delivered rbLf to improve dysregulated gut health in infant mouse pups. With the successful completion of both aims, we expect to demonstrate rbLf promotes immune and gut interactions that maintain biological activity and efficacy as compared to cMDLf. The scope of work is designed to support regulatory approval and expedite TurtleTree’s path to market for the safe and effective application of advancing infant health.

项目总结/文摘