R01HD093729-05 MPI: Mcmanaman, Monks

09/01/2018-05/31/2023        RNICHD

Molecular Determinants of Lactation Success

Breastfeeding provides neonates with essential nutrients for growth and development, and protection against postnatal and long-term health risks including morbidities associated with bacterial and viral infections, childhood obesity, and type-2 diabetes. Comparatively few mothers in the United States, particularly those who are overweight or obese, successfully breastfeed their children for the recommended period of time due to failure to either initiate or maintain lactation. Interference with milk lipid secretion is linked to impaired milk secretion and lactation failure in humans and animal models. This project uses novel transgenic mouse models to investigate how milk lipid secretion regulates lactation success and to delineate the molecular mechanisms that regulate this function. We anticipate that greater understanding the basic mechanisms controlling milk lipid secretion as proposed in this application will fill conceptual and experimental gaps that pose barriers to understanding biological mechanisms controlling of lactation success in humans.

1. Martin Carli JF, Dzieciatkowska M, Hernandez TL, Monks J, McManaman JL. Comparative proteomic analysis of human milk fat globules and paired membranes and mouse milk fat globules identifies core cellular systems contributing to mammary lipid trafficking and secretion. Front Mol Biosci. 2023 Dec 18;10:1259047. doi: 10.3389/fmolb.2023.1259047. PMID: 38169886; PMCID: PMC10759240.​
2. Neville MC, Demerath EW, Hahn-Holbrook J, Hovey RC, Martin-Carli J, McGuire MA, Newton ER, Rasmussen KM, Rudolph MC, Raiten DJ.Parental factors that impact the ecology of human mammary development, milk secretion, and milk composition-a report from "Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN)" Working Group 1.Am J Clin Nutr. 2023 Apr;117 Suppl 1(Suppl 1):S11-S27. doi: 10.1016/j.ajcnut.2022.11.026. PMID: 37173058; PMCID: PMC10232333.​
3. Monks J, Ladinsky MS, McManaman JL. Organellar Contacts of Milk Lipid Droplets. Contact (Thousand Oaks). 2020 Jan-Dec;3. doi: 10.1177/2515256419897226. Epub 2020 Jan 23. PubMed PMID: 32232194; PubMed Central PMCID: PMC7105144.
4. Martin Carli JF, Trahan GD, Jones KL, Hirsch N, Rolloff KP, Dunn EZ, Friedman JE, Barbour LA, Hernandez TL, MacLean PS, Monks J, McManaman JL, Rudolph MC. Single Cell RNA Sequencing of Human Milk-Derived Cells Reveals Sub-Populations of Mammary Epithelial Cells with Molecular Signatures of Progenitor and Mature States: a Novel, Non-invasive Framework for Investigating Human Lactation Physiology. J Mammary Gland Biol Neoplasia. 2020 Dec;25(4):367-387. doi: 10.1007/s10911-020-09466-z. Epub 2020 Nov 20. Review. PubMed PMID: 33216249; PubMed Central PMCID: PMC8016415.
5. Ladinsky MS, Mardones GA, Orlicky DJ, Howell KE, McManaman JL. Electron Tomography Revels that Milk Lipids Originate from Endoplasmic Reticulum Domains with Novel Structural Features. J Mammary Gland Biol Neoplasia. 2019 Dec; 24(4):293-304. PMID: 31709487.
6. Monks J, Orlicky DJ, Stefanski AL, Libby AE, Bales ES, Rudolph MC, Johnson GC, Sherk VD, Jackman MR, Williamson K, Carlson NE, MacLean PS, McManaman JL. Maternal obesity during lactation may protect offspring from high fat diet-induced metabolic dysfunction. Nutr Diabetes. 2018 Apr 25;8(1):18. doi: 10.1038/s41387-018-0027-z. PubMed PMID: 29695710; PubMed Central PMCID: PMC5916951.
7. Hazegh KE, Nemkov T, D'Alessandro A, Diller JD, Monks J, McManaman JL, Jones KL, Hansen KC, Reis T. Correction: An autonomous metabolic role for Spen. PLoS Genet. 2018 03; 14(3):e1007266. PMID: 29509756.
8. Neville MC, Monks J. The Cell Biology of the Lactating Mammary Epithelium, in M. K. Skinner (Ed.), Encyclopedia of Reproduction. vol. 2. [Internet]. Academic Press: Elsevier; 2018 January. pp. 779–785. Available from: https://doi.org/10.1016/B978-0-12-801238-3.64419-7. DOI: 10.1016/B978-0-12-801238-3.64419-7.
9. Xiong X, Bales ES, Ir D, Robertson CE, McManaman JL, Frank DN, Parkinson J. Perilipin-2 modulates dietary fat-induced microbial global gene expression profiles in the mouse intestine. Microbiome. 2017 09 06; 5(1):117. PMID: 28877764.
10. Hazegh KE, Nemkov T, D'Alessandro A, Diller JD, Monks J, McManaman JL, Jones KL, Hansen KC, Reis T. An autonomous metabolic role for Spen. PLoS Genet. 2017 Jun;13(6):e1006859. doi: 10.1371/journal.pgen.1006859. eCollection 2017 Jun. PubMed PMID: 28640815; PubMed Central PMCID: PMC5501677.
11. Libby AE, Bales E, Orlicky DJ, McManaman JL. Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome. J Biol Chem. 2016 Nov 11; 291(46):24231-24246. PMID: 27679530.
12. Monks J, Dzieciatkowska M, Bales ES, Orlicky DJ, Wright RM, McManaman JL. Xanthine oxidoreductase mediates membrane docking of milk-fat droplets but is not essential for apocrine lipid secretion. J Physiol. 2016 Oct 15;594(20):5899-5921. doi: 10.1113/JP272390. Epub 2016 Aug 3. PubMed PMID: 27357166; PubMed Central PMCID: PMC5063925.
13. Frank DN, Bales ES, Monks J, Jackman MJ, MacLean PS, Ir D, Robertson CE, Orlicky DJ, McManaman JL. Perilipin-2 Modulates Lipid Absorption and Microbiome Responses in the Mouse Intestine. PLoS One. 2015;10(7):e0131944. doi: 10.1371/journal.pone.0131944. eCollection 2015. PubMed PMID: 26147095; PubMed Central PMCID: PMC4493139.
14. Neville MC, Webb P, Ramanathan P, Mannino MP, Pecorini C, Monks J, Anderson SM, MacLean P. The insulin receptor plays an important role in secretory differentiation in the mammary gland. Am J Physiol Endocrinol Metab. 2013 Nov 1;305(9):E1103-14. doi: 10.1152/ajpendo.00337.2013. Epub 2013 Aug 27. PubMed PMID: 23982156; PubMed Central PMCID: PMC3840206.
15. Crunk AE, Monks J, Murakami A, Jackman M, Maclean PS, Ladinsky M, Bales ES, Cain S, Orlicky DJ, McManaman JL. Dynamic regulation of hepatic lipid droplet properties by diet. PLoS One. 2013;8(7):e67631. doi: 10.1371/journal.pone.0067631. Print 2013. PubMed PMID: 23874434; PubMed Central PMCID: PMC3708958.
16. Orlicky DJ, Monks J, Stefanski AL, McManaman JL. Dynamics and molecular determinants of cytoplasmic lipid droplet clustering and dispersion. PLoS One. 2013;8(6):e66837. doi: 10.1371/journal.pone.0066837. Print 2013. PubMed PMID: 23825572; PubMed Central PMCID: PMC3692517.