Menopause: Decreased Response to Increasing Inflammation

更年期：对炎症加剧的反应减弱

• 批准号: 7068738
• 负责人: Adriana Caterina Maggi
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF MILAN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068738
• 关键词: aging; biological models; clinical research; estrogen receptors; estrogens; female; genetically modified animals; hormone regulation /control mechanism; human subject; immunosenescence; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; menopause; model design /development; polymerase chain reaction; receptor expression; women' s health

DESCRIPTION (provided by applicant): The long-term goal of our research is to find treatments for the prevention of the disorders associated with menopause which are safer and more efficacious than present hormone replacement therapy (HRT). The failure of present HRT to fulfill medical and women's needs has to be ascribed to an insufficient knowledge of the biology of menopause. The aim of our research is focused on the understanding the consequences of cessation of ovarian functions on the physiology of non-reproductive organs such as bone, brain, arteries and fat. In particular our studies and the studies proposed in the present project will focus on the effects of estrogen decreased production at menopause transition and after in non-reproductive organs. Given recent results demonstrating that in non-reproductive organs of fertile female mice estrogen receptors (ERs) are activated by factors other than estrogens, our Specific Aim #1 will focus on assessing the extent to which ERs are transcriptionally active during menopause transition and after. We will then try to identify the factor(s) involved in ER activation. This part of the project relates to questions which so far could be addressed only partially with the current technology. The generation of a novel model of reporter system, the ERE-Luc mouse, will enable us to precisely quantify ER activity in the organs of interest and facilitate the search of factors involved in ER unliganded activation. Specific Aim #2 will give us the opportunity to test an original hypothesis that would explain the widespread protective effects provided by the estrogen-ER system. This hypothesis is based on numerous very recent observations made in ours and several other groups showing that estrogens and cognate receptors may exert a strong anti-inflammatory action by inhibiting the immune response of cells of the monocyte lineage. We here propose that menopause consists in a decreased response to increased inflammation. We will test this hypothesis by the direct assessment of ER relevance on macrophage activity through the generation of a novel conditional ERalpha K.O. mouse. Furthermore, using brain as a paradigmatic non-reproductive organ, we will measure basal and induced activity of brain inflammatory cells. Finally, the specific involvement of ER anti-inflammatory activity in the development of menopause-associated diseases will be tested with the study of the activity in menopause of another class of intracellular receptors devoted to the control of inflammation, the PPARs.

描述(申请人提供)：我们研究的长期目标是找到比目前的激素替代疗法(HRT)更安全和更有效的预防与更年期相关的疾病的治疗方法。目前的激素替代疗法未能满足医学和妇女的需要，必须归因于对更年期生物学知识的不足。我们的研究目的是了解卵巢功能停止对骨、脑、动脉和脂肪等非生殖器官的生理影响。特别是，我们的研究和本项目中提出的研究将集中在绝经过渡期间和之后雌激素减少对非生殖器官的影响。鉴于最近的研究结果表明，在有生育能力的雌性小鼠的非生殖器官中，雌激素受体(ER)被雌激素以外的因素激活，我们的具体目标#1将集中在评估更年期过渡期间和之后ER转录活跃的程度。然后我们将尝试确定参与ER激活的因素(S)。该项目的这一部分涉及迄今只能用现有技术部分解决的问题。一种新的报告系统模型ERERLUC小鼠的产生将使我们能够精确地量化感兴趣器官中的ER活性，并有助于寻找参与ER去连接激活的因素。具体目标#2将使我们有机会测试一个原始假设，该假设将解释雌激素-雌激素受体系统提供的广泛保护作用。这一假说是基于我们和其他几个小组最近的大量观察结果，表明雌激素和同源受体可能通过抑制单核细胞系细胞的免疫反应而发挥强大的抗炎作用。我们在此提出，更年期包括对炎症增加的反应减弱。我们将通过直接评估ER与巨噬细胞活性的相关性来检验这一假设，方法是通过产生一只新的条件性ERAlpha K.O.小鼠。此外，将脑作为一个聚合的非生殖器官，我们将测量脑炎性细胞的基础和诱导活性。最后，将通过对另一类致力于控制炎症的细胞内受体PPAR在更年期的活性的研究来检验ER抗炎活性在更年期相关疾病的发展中的具体参与。