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

项目总结/摘要 该INBRE行政补充文件扩大了爱达荷州开展妇女健康研究的能力。 这项拟议的研究在母INBRE奖#P20 GM 103408的范围内。它符合广泛的 和包容性的爱达荷州INBRE科学主题的“细胞信号”，发展调查研究能力， 为有能力的学生提供研究机会。这项研究关注的是母亲哺乳不良 糖尿病患者常出现的症状。这种代谢疾病发生在6-9%的怀孕 在美国，不成比例地影响农村人口和种族和少数民族，这构成了 大约占爱达荷州人口的20%该项目的假设是，糖尿病下调关键基因， 减少参与乳汁合成的乳腺蛋白质，影响线粒体生物合成， 呼吸线粒体变化可导致氧化代谢受损、氧化应激和 因此泌乳性能差。从拟议项目中获得的基本知识可能 导致有效的药物治疗策略，以改善母亲和婴儿的临床结果。 在世界范围内，母乳喂养率继续落后于美国儿科学会和世界卫生组织 组织目标。母乳喂养率低是一个公共卫生问题， 和产妇保健。产奶开始延迟和乳汁供应不足通常发生在妊娠期， 1型和2型糖尿病。目前还不清楚母亲糖尿病如何损害泌乳性能;然而， 新出现的证据指出，线粒体功能障碍可能是这些影响的驱动因素。线粒体 多种组织中的功能障碍和随之发生的氧化应激与糖尿病病理学有关。 此外，最佳的线粒体功能使得能够为乳汁提供所需的能量和底物 合成.该假设将在两个具体目标中得到检验。第一个目标是确定结构和功能 与糖尿病相关的乳腺线粒体变化。实验将使用大鼠妊娠模型， 与年龄匹配的对照组大鼠相比，乳汁体积和成分将作为以下指标进行分析： 泌乳性能线粒体形态和密度的差异将通过电子显微镜成像 显微镜线粒体功能的差异将通过呼吸和氧化应激来测量 乳腺组织的差异。第二个目标是研究不良反应的分子途径。 妊娠期糖尿病对哺乳性能的影响。代谢差异将通过定量 RT-PCR和无标记鸟枪蛋白质组学。这项研究将增加学生的数量， 妇女健康相关的生物医学科学，并为R 01提案提供初步数据。长期 目标将是针对哺乳不良制定有针对性的干预措施，以改善婴儿和产妇健康。

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.