Idaho INBRE Women's health: contribution of mammary mitochondrial dysfunction to poor milk production in diabetic mothers

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Project Summary/Abstract This INBRE administrative supplement expands the capacity of Idaho to conduct women’s health research. This proposed research is within the scope of the parent INBRE award #P20 GM103408. It fits within the broad and inclusive Idaho INBRE scientific theme of ‘cell signaling’, develops investigator research capacity, and provides research opportunities to capable students. The study focuses on poor maternal lactation performance that often accompanies diabetes mellitus. This metabolic disease occurs in 6-9% of pregnancies in the U.S and disproportionately affects rural populations and racial and ethnic minorities, which make up roughly 20% of Idaho’s population. The project hypothesis is that diabetes downregulates key genes that reduce mammary gland proteins involved in milk synthesis and affects mitochondrial biogenesis and respiration. Mitochondrial changes can lead to impaired oxidative metabolism, oxidative stress, and consequently poor lactation performance. The fundamental knowledge gained from the proposed project may lead to effective pharmacotherapeutic strategies to improve clinical outcomes for mothers and infants. Worldwide, breastfeeding rates continue to lag behind American Academy of Pediatrics and World Health Organization targets. Low breastfeeding rates are a public health concern, with consequences for both infant and maternal health. A delay in the onset of milk production and low milk supply often occur with gestational, type 1, and type 2 diabetes. It is unclear how maternal diabetes impairs lactation performance; however emerging evidence points to mitochondrial dysfunction as a likely driver of these effects. Mitochondrial dysfunction and consequent oxidative stress in multiple tissues have been linked to diabetes pathology. Further, optimal mitochondrial function enables provisioning of needed energy and substrates for milk synthesis. The hypothesis will be tested in two specific aims. The first aim will identify structural and functional changes in mammary mitochondria associated with diabetes. Experiments will use a rat model of gestational diabetes compared to age-matched control rats. Milk volume and composition will be analyzed as metrics of lactation performance. Disparities in mitochondrial morphology and density will be imaged by electron microscopy. Differences in mitochondrial function will be measured by respiration and oxidative stress differences in mammary tissues. The second aim will investigate the molecular pathways underlying adverse effects of gestational diabetes on lactation performance. Metabolic disparities will be identified by quantitative RT-PCR and label-free shotgun proteomics. This study will increase the number of students training in women’s health-related biomedical sciences and provide preliminary data for an R01 proposal. The long-term goal will be to develop targeted interventions for poor lactation to improve infant and maternal health.