Project-003

项目-003

• 批准号: 10676294
• 负责人: Kristin Shirey Edwards
• 金额: $ 26.89万
• 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/10676294
• 关键词: Abdominal Pain; Accounting; 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.

多囊卵巢综合征（PCOS）是一种影响7-10％的妇女生殖年份的疾病， 在美国，约有500万妇女。大约有80％的PCO妇女患有 高传射血症增加了发生合并症的风险，例如肥胖，慢性炎症， 血压升高，II型糖尿病，胰岛素抵抗，血脂异常和高丧血血症。此外， 大约42％的PCOS妇女患有胃肠道（GI）症状，例如腹痛， 便秘，腹泻和/或腹胀。这些症状中有许多与亚急性胃肠道炎症有关。 二甲双胍是PCOS女性代谢功能障碍的常见治疗方法，会引起GI副作用，通常 导致患者不遵守治疗。但是，有助于这些GI的机制 症状未知。我在高雄激素女性（HAF）大鼠模型中令人兴奋的初步数据 PCOS显示线粒体功能障碍，线粒体活性氧（MTROS）和 结肠炎症。此外，我的初步数据表明，结肠MTROS和炎症是 给定二甲双胍的HAF大鼠进一步增加。然后，我们假设：1）亚急性GI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害 氧化磷酸化，导致MTROS增加，肠道营养不良和炎症进一步 二甲双胍加剧； 2）使用线粒体靶向抗氧化剂（例如Mitotempo）将使用 提高线粒体功能，减少MTROS和炎症，从而阻止亚急性的发展 PCOS妇女的GI炎症。这些假设将被测试我们的表征和临床相关的良好特征 PCOS模型，HAF大鼠，在以下特定目的中：目标1：测试结肠线粒体的假设 HAF大鼠的功能障碍和MTRO的增加与肠道营养不良和亚急性GI有关 炎症，线粒体靶向的抗氧化剂疗法（如Mitotempo）将减弱这些 变化；目标2：测试HAF大鼠中二甲双胍加剧结肠线粒体的假设 功能障碍增加肠道营养不良和炎症，并添加抗氧化剂，例如mitotempo， 将通过二甲双胍提高线粒体功能。