Investigating the Role of Lipid Droplet Docking in Lactation Initiation and Milk Secretion

PROJECT SUMMARY Milk is a complex fluid capable of providing total nutrition of the human infant for 6 months or longer, as well as enhanced protection against infection and common childhood illnesses during the critical early postnatal period. Successful initiation of lactation, called secretory activation, requires hormonal signaling that initiates synthesis and secretion of milk products in secretory mammary epithelial cells and stimulates contractile activity in surrounding myoepithelial cells. Disruptions from maternal obesity, premature birth, or delivery-related stresses are associated with impaired secretory activation and poor lactation performance. Since there are no available treatments for low-milk supply, it is critically important to continue to explore basic molecular mechanisms of mammary gland biology and milk secretion. Specific aims in this proposal explore (1) the role of milk fat secretion in secretory activation, (2) the crosstalk between the secretory cells and myoepithelial cells at secretory activation, and (3) how obesity disrupts milk fat secretion and secretory activation. The proposed studies use mouse models of obesity, quantitative intravital and super-resolution imaging, exploratory and hypothesis-driven omics studies and innovative physiological models to define the cellular mechanisms involved in secretory activation. Genetically modified mice and pharmacological agents will be used to modify specific signaling pathways which may stimulate or inhibit milk secretion. The resulting information will provide a new paradigm for understanding the causes of delayed initiation of lactation in humans, allowing the development of evidence- based strategies to address lactation insufficiency and increase breastfeeding success rates.