Inflammatory triggers of polycystic ovarian syndrome.

我们对多囊卵巢综合征（PCOS）如何发展的理解存在根本性的差距。这些知识对于预防多囊卵巢综合征和合并症（如2型糖尿病和心血管疾病）至关重要。多囊卵巢综合征患者表现为低度炎症状态，可能由高胰岛素血症、肥胖或其他因素引发。该提案的中心假设是多囊卵巢综合征相关的低级别慢性炎症导致卵巢功能障碍。这一假设是根据申请人实验室产生的初步数据制定的，并将通过三个具体目标进行测试：1)确定PCOS小鼠模型中炎症是否先于卵巢功能障碍。2)确定基因抑制炎症是否可以预防PCOS症状的发展。3)确定药物抑制炎症是否可以预防PCOS症状的发展。在第一个目标下，申请人开发的一种新的PCOS小鼠模型将用于检查雄激素过量和炎症的年龄依赖性发作。在第二个目标下，缺乏炎症反应的小鼠品系将用于测试慢性免疫系统激活是否导致多囊卵巢综合征。最后，第三个目的是测试关键炎症通路的药理抑制是否能抑制或治疗多囊卵巢综合征。这项拟议的研究将是首次使用动物模型直接测试炎症是否在多囊卵巢综合征的发展中起重要作用。通过确定多囊卵巢综合征发展的致病因素和测试一种新的药物治疗方法，这些结果有可能改变目前的研究和临床实践范式。这项研究的发现可能有助于识别有多囊卵巢综合征风险的女性，预防其发展和合并症，从而降低医疗成本，延长生命。

A fundamental gap exists in our understanding of how polycystic ovarian syndrome (PCOS) develops. This knowledge is essential to preventing PCOS and co-morbidities such as type 2 diabetes and cardiovascular disease. PCOS patients exhibit a low-grade inflammatory state, which may be triggered by hyperinsulinemia, obesity, or other factors. The proposal's central hypothesis is that low-grade, chronic inflammation associated with PCOS causes ovarian dysfunction. This hypothesis has been formulated from preliminary data produced in the applicant's laboratory and will be tested by pursuing three specific aims: 1) Determine whether inflammation precedes ovarian dysfunction in a potential mouse model of PCOS. 2) Determine whether genetic inhibition of inflammation can prevent the development of PCOS symptoms. 3) Determine whether pharmacological inhibition of inflammation can prevent the development of PCOS symptoms. Under the first aim, a new mouse model of PCOS developed by the applicants will be used to examine the age-dependent onset of androgen excess and inflammation. Under the second aim, mouse strains lacking an inflammatory response will be used to test whether chronic immune system activation leads to PCOS. Finally, the third aim will test whether pharmacological inhibition of a key inflammatory pathway inhibits or treats PCOS. The proposed studies will be the first direct test of whether inflammation plays an essential role in PCOS development using an animal model. The results have the potential to shift current research and clinical practice paradigms by identifying a causative factor in PCOS development and testing a novel pharmacological treatment for the disorder. The findings from this research may help to identify women at risk for PCOS and prevent its development and co-morbidities, thus reducing healthcare costs and extending lives.