Project-003

项目-003

• 批准号: 10657011
• 负责人: Kristin Shirey Edwards
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-08 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657011
• 关键词: Abdominal Pain; Accounting; Acute; Affect; Androgens; Antioxidants; Attenuated; Chronic; Colon; Constipation; Data; Development; Diarrhea; Dyslipidemias; Female; Hyperandrogenemia; Impairment; Inflammation; Insulin Resistance; Link; Mediating; Metabolic dysfunction; Metformin; Mississippi; Mitochondria; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Phosphorylation; Patient Noncompliance; Perinatal; Phase; Polycystic Ovary Syndrome; Rattus; Reactive Oxygen Species; Research; Risk; Testing; United States; Woman; antioxidant therapy; associated symptom; blood pressure elevation; clinically relevant; common treatment; comorbidity; gastrointestinal; gastrointestinal symptom; gut dysbiosis; gut inflammation; improved; mitochondrial dysfunction; prevent; reproductive; side effect

Polycystic ovarian syndrome (PCOS) is a condition that affects 7-10% of women in their reproductive years, accounting for roughly 5 million women in the United States. Approximately, 80% of PCOS women suffer from hyperandrogenemia increasing the risk for developing comorbidities, such as obesity, chronic inflammation, increased blood pressure, type II diabetes, insulin resistance, dyslipidemias, and hyperleptinemia. In addition, approximately 42% of PCOS women suffer from gastrointestinal (GI) symptoms, such as abdominal pain, constipation, diarrhea, and/or bloating. Many of these symptoms are associated with sub-acute GI inflammation. Metformin, a common treatment for metabolic dysfunction in PCOS women, causes GI side effects, often resulting in patient non-compliance with treatment. However, the mechanisms that contribute to these GI symptoms are unknown. My exciting preliminary data in the hyperandrogenemic female (HAF) rat model of PCOS show mitochondrial dysfunction, increased mitochondrial reactive oxygen species (mtROS), and inflammation in the colon. Furthermore, my preliminary data show that colonic mtROS and inflammation are further increased in HAF rats given metformin. We hypothesize then: 1) the development of sub-acute GI inflammation in PCOS women is due to androgen- and AR-mediated impairment of colonic mitochondrial oxidative phosphorylation, leading to increased mtROS, gut dysbiosis, and inflammation that is further exacerbated by metformin; 2) the use of a mitochondrial targeted antioxidant therapy, such as MitoTEMPO, will improve mitochondrial function, decrease mtROS and inflammation, thus preventing development of sub-acute GI inflammation in PCOS women. These hypotheses will be tested our well characterized and clinically relevant model of PCOS, the HAF rat, in the following specific aims: Aim 1: To test the hypothesis that colon mitochondrial dysfunction and increased mtROS in HAF rats is linked to increased gut dysbiosis and sub-acute GI inflammation, and that mitochondrial-targeted antioxidant therapies, such as MitoTEMPO, will attenuate these changes; Aim 2: To test the hypothesis that metformin in the HAF rat exacerbates colonic mitochondrial dysfunction increasing gut dysbiosis and inflammation, and that addition of an antioxidant, such as MitoTEMPO, will improve the mitochondrial function with metformin.

多囊卵巢综合症 (PCOS) 是一种影响 7-10% 育龄女性的疾病， 美国大约有 500 万女性。大约 80% 的 PCOS 女性患有 高雄激素血症会增加患合并症的风险，例如肥胖、慢性炎症、 血压升高、II型糖尿病、胰岛素抵抗、血脂异常和高瘦素血症。此外， 大约 42% 的 PCOS 女性患有胃肠道 (GI) 症状，例如腹痛、 便秘、腹泻和/或腹胀。其中许多症状与亚急性胃肠道炎症有关。 二甲双胍是治疗 PCOS 女性代谢功能障碍的常用药物，通常会引起胃肠道副作用 导致患者不配合治疗。然而，导致这些 GI 的机制 症状未知。我在高雄激素血症雌性 (HAF) 大鼠模型中获得的令人兴奋的初步数据 PCOS 表现出线粒体功能障碍、线粒体活性氧 (mtROS) 增加和 结肠炎症。此外，我的初步数据显示结肠 mtROS 和炎症是 给予二甲双胍的 HAF 大鼠进一步增加。我们假设：1）亚急性胃肠道的发展 PCOS 女性的炎症是由于雄激素和 AR 介导的结肠线粒体损伤所致 氧化磷酸化，导致 mtROS 增加、肠道菌群失调和炎症，进一步加剧 二甲双胍加剧； 2) 使用线粒体靶向抗氧化疗法，例如 MitoTEMPO，将 改善线粒体功能，减少 mtROS 和炎症，从而预防亚急性疾病的发展 多囊卵巢综合症女性的胃肠道炎症。这些假设将经过我们充分表征和临床相关的检验 PCOS 模型（HAF 大鼠）的具体目标如下： 目标 1：检验结肠线粒体 HAF 大鼠的功能障碍和 mtROS 增加与肠道菌群失调和亚急性胃肠道的增加有关 炎症，而线粒体靶向抗氧化疗法（例如 MitoTEMPO）将减轻这些炎症 变化；目标 2：检验二甲双胍在 HAF 大鼠中加剧结肠线粒体的假设 功能障碍会增加肠道菌群失调和炎症，并且添加抗氧化剂，例如 MitoTEMPO， 与二甲双胍一起改善线粒体功能。