Menopause: Decreased Response to Increasing Inflammation

更年期：对炎症加剧的反应减弱

• 批准号: 7457801
• 负责人: Adriana Caterina Maggi
• 金额: $ 16.85万
• 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/7457801
• 关键词: Address; Affect; Aging; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; Arteriosclerosis; Automobile Driving; Biology; Brain; Cardiovascular Diseases; Cells; Class; Clinic; Collaborations; Competence; Complex; Dementia; Depth; Development; Diabetes Mellitus; Disease; Engineering; Ensure; Environment; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Europe; European; Failure; Fatty acid glycerol esters; Female; Future; Generations; Goals; Gynecology; Hand; Hormone replacement therapy; Human; Immune response; Inflammation; Inflammatory; Kidney; Knowledge; Ligands; Luciferases; Maps; Measures; Medical; Menopause; Methodology; Methods; Modeling; Mus; Mutant Strains Mice; Onset of illness; Organ; Osteoporosis; Outcome; Ovarian; Ovary; Pathology; Perimenopause; Peroxisome Proliferator-Activated Receptors; Physiological; Physiology; Process; Production; Qualifying; Reagent; Receptor Activation; Replacement Therapy; Reporter; Reporter Genes; Research; Research Personnel; Research Project Grants; Resistance; Solid; Steroid Receptors; System; Technology; Testing; Tissues; Transcriptional Activation; Up-Regulation; Woman; base; bone; design; disorder prevention; innovation; insight; interest; macrophage; monocyte; new technology; novel; promoter; protective effect; receptor; reproductive; response; stem; theories; therapy design

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（由申请人提供）：我们研究的长期目标是找到预防绝经相关疾病的治疗方法，这些方法比目前的激素替代疗法（HRT）更安全，更有效。目前HRT未能满足医疗和妇女的需要，必须归因于对更年期生物学的认识不足。我们研究的目的是了解卵巢功能停止对非生殖器官（如骨骼，大脑，动脉和脂肪）生理学的影响。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和非生殖器官中雌激素产生减少的影响。鉴于最近的研究结果表明，在非生殖器官的生育雌性小鼠雌激素受体（ER）激活的因素以外的雌激素，我们的具体目标#1将集中在评估的程度ER是转录活跃在绝经过渡期和之后。然后，我们将尝试确定参与ER激活的因素。项目的这一部分涉及到目前为止只能用现有技术部分解决的问题。ERE-Luc小鼠是一种新的报告系统模型，它的建立将使我们能够精确地定量研究ER在相关器官中的活性，并有助于寻找ER非配体激活的相关因素。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-ER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研究小组最近的大量观察结果，这些观察结果表明雌激素和同源受体可能通过抑制单核细胞谱系细胞的免疫反应而发挥强烈的抗炎作用。我们在这里提出，绝经期包括在一个减少的反应增加炎症。我们将通过产生新的条件性ER α K.O.直接评估ER与巨噬细胞活性的相关性来检验这一假设。老鼠.此外，使用脑作为典型的非生殖器官，我们将测量脑炎症细胞的基础和诱导活性。最后，ER抗炎活性在绝经期相关疾病的发展中的具体参与将通过研究另一类致力于控制炎症的细胞内受体PPARs在绝经期的活性来测试。