Inflammatory triggers of polycystic ovarian syndrome.

多囊卵巢综合征的炎症触发因素。

• 批准号: 8441506
• 负责人: Jennifer Wootton Hill
• 金额: $ 17.74万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-08 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441506
• 关键词: Affect; Androgens; Animal Model; Anovulation; Anti-Inflammatory Agents; Anti-inflammatory; B-Lymphocytes; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Comorbidity; Control Animal; Data; Development; Disease; Etiology; Exhibits; Fatty acid glycerol esters; Fertility; Functional disorder; Genetic; Health Care Costs; Hyperinsulinism; Immune; Immune system; Impairment; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Knowledge; Laboratories; Metabolic; Modeling; Mouse Strains; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovarian; Ovarian Cysts; Ovary; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Play; Polycystic Ovary Syndrome; Premenopause; Prevention strategy; Rag1 Mouse; Research; Risk; Role; Steroid biosynthesis; Steroids; Symptoms; Syndrome; T-Lymphocyte; Testing; Tissues; Visceral; Woman; age related; cell mediated immune response; clinical practice; cytokine; human disease; macrophage; mouse model; novel; prevent; reproductive; salicylsalicylic acid; steroid hormone; theca cell; treatment strategy

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.

我们对多囊卵巢综合征（PCOS）如何发生的理解存在根本性的差距。这些知识对于预防 PCOS 和 2 型糖尿病和心血管疾病等并发症至关重要。 PCOS 患者表现出低度炎症状态，这可能是由高胰岛素血症、肥胖或其他因素引发的。该提案的中心假设是，与多囊卵巢综合症相关的低度慢性炎症会导致卵巢功能障碍。这一假设是根据申请人实验室产生的初步数据制定的，并将通过追求三个具体目标进行测试：1）确定在潜在的 PCOS 小鼠模型中炎症是否先于卵巢功能障碍。 2) 确定炎症的基因抑制是否可以预防 PCOS 症状的发展。 3) 确定炎症的药物抑制是否可以预防 PCOS 症状的发展。第一个目标是，申请人开发的新的多囊卵巢综合症小鼠模型将用于检查雄激素过多和炎症的年龄依赖性发作。第二个目标将使用缺乏炎症反应的小鼠品系来测试慢性免疫系统激活是否会导致多囊卵巢综合症。最后，第三个目标将测试关键炎症途径的药理抑制是否可以抑制或治疗多囊卵巢综合症。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症的发展中发挥重要作用。这些结果有可能通过确定多囊卵巢综合症发展的致病因素并测试针对该疾病的新型药物治疗方法来改变当前的研究和临床实践范式。这项研究的结果可能有助于识别患有多囊卵巢综合症的女性，并预防其发展和合并症，从而降低医疗费用并延长寿命。