Inflammatory triggers of polycystic ovarian syndrome.

多囊卵巢综合征的炎症触发因素。

• 批准号: 8303668
• 负责人: Jennifer Wootton Hill
• 金额: $ 18.66万
• 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/8303668
• 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）如何发展的理解存在着根本的差距。这些知识对于预防PCOS和合并症（例如2型糖尿病和心血管疾病）至关重要。 PCOS患者表现出低度炎症状态，可能由高胰岛素血症，肥胖或其他因素触发。该提案的中心假设是，与PCOS相关的低度，慢性炎症会引起卵巢功能障碍。该假设是由申请人实验室中产生的初步数据提出的，并将通过追求三个具体目的来测试：1）确定炎症是否在潜在的PCOS小鼠模型中卵巢功能障碍之前。 2）确定遗传抑制炎症是否可以防止PCOS症状的发展。 3）确定药理学抑制炎症是否可以防止PCOS症状的发展。在第一个目标下，申请人开发的PCOS的新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菌株将用于测试慢性免疫系统激活是否导致PCOS。最后，第三个目标将测试药理抑制关键炎症途径是否抑制或治疗PCOS。拟议的研究将是对使用动物模型在PCOS发育中发挥重要作用的首次直接测试。该结果有可能通过鉴定PCOS发育中的致病因素并测试对该疾病的新药理治疗方法来改变当前的研究和临床实践范例。这项研究的发现可能有助于确定有PCOS风险的妇女，并防止其发展和合并症，从而降低医疗保健成本并延长寿命。