Investigating obesity-induced altered ovarian intracellular signaling

摘要：这项研究是关于气候变化对健康的影响，特别是与女性有关 精瘦和肥胖女性的生殖和一般健康。由于肥胖影响了约40%的女性，而且 这项提案对少数族裔女孩和妇女的影响不成比例，与 气候变化和健康倡议。这项工作解决了已确定的相关领域的理解 气候变化应激对生殖发育的影响及多种化学物质的评价 (DMBA)和非化学应激源(肥胖和热应激)。气候变化和 严重HS事件的伴随频率有增无减，因此了解HS对卵巢的影响 功能是非常需要的。基廷博士在这项研究中具有独特的地位，这是因为她在 卵巢生物学的这一领域(关于热应激生物学的20篇出版物，其中大多数涉及 生殖)和进行这些研究的技术可行性。假设是热应激会导致 高胰岛素血症改变卵巢类固醇激素合成、DNA修复、氧化应激和化学物质 生物转化蛋白的丰度，加速了DMBA暴露期间的卵巢毒性，这将 相对于瘦小的小鼠，肥胖的小鼠会更高。这一假设是基于我们强劲的初步数据 母猪生物医学模型及其与肥胖期间观察到的代谢变化的相关性。这 补充将生成数据，为未来探索热应激对环境的影响铺平道路 使用易于处理的小鼠模型深入研究特定途径的卵毒性。

Abstract: The research proposed is on Health Effects of climate change, specifically related to female reproductive and general health, in lean and obese females. Since obesity affects ~40% of women, and disproportionately impacts minority girls and women, this proposal is relevant to the Health Equity aspects of the climate change and health initiative. This work addresses \ the identified relevant areas of understanding the effects of climate-change-induced stress on reproduction and development and assesses multiple chemical (DMBA) and non-chemical stressors (obesity and heat stress) across the lifespan. Climate change and accompanying frequency of severe HS events is unabating, thus, understanding impacts of HS on ovarian function is desperately needed. Dr. Keating is uniquely positioned for this study due to her scientific record in this area of ovarian biology (twenty publications on heat stress biology with the majority related to reproduction) and the technical feasibility to conduct these studies. The hypothesis is that heat stress will cause hyperinsulinemia, altering ovarian steroidogenic, DNA repair, oxidative stress and chemical biotransformation protein abundance, accelerating ovarian toxicity during DMBA exposure, and this will be heightened in obese relative to lean mice. This hypothesis is based upon our strong preliminary data in female pig biomedical models and the relevance to the metabolic changes observed during obesity. This supplement will generate data to pave the way for future exploration into the additive impact of heat stress on ovotoxicity using tractable mouse models to delve into specific pathways.