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Estrogen Modulates Injury-Induced Inflammation

雌激素调节损伤引起的炎症

基本信息

批准号：
7249354
负责人：
Suzanne Oparil
金额：
$ 34.37万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7249354
关键词：
Acute Address Adhesions Adipocytes Adventitious Tissue Aging Agonist Anti-Inflammatory Agents Anti-inflammatory Appearance Arterial Injury Arteries Biological Markers Blood Vessels Carotid Arteries Cell Adhesion Molecules Cells Chemotactic Factors Conditioned Culture Media Development Elastases Endopeptidases Enzymes Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Event Fibroblasts Flow Cytometry Free Radicals Hour In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury Leukocytes Medial Mediating Mediator of activation protein Medroxyprogesterone 17-Acetate Menopause Microarray Analysis Modeling Molecular NADPH Oxidase Numbers Ovarian hormone Oxidants Pancreatic Elastase Pathogenesis Peptide Hydrolases Pericytes Play Process RNA Interference Rattus Reaction Recruitment Activity Research Research Personnel Rodent Model Role Signal Transduction Site Smooth Muscle Myocytes Specificity Synthetic Progestogens T-Lymphocyte Testing Tissues Tunica Adventitia Vascular Diseases Vascular remodeling Woman base cell type chemokine cytokine experience granulocyte hormone therapy in vivo injured leukocyte activation macrophage migration monocyte neointima formation neutrophil novel novel therapeutics programs protective effect response response to injury

项目摘要

DESCRIPTION (provided by applicant): Inflammation plays an important role in the pathogenesis of many forms of vascular disease, and menopausal hormone therapy has been shown to modulate the expression of inflammatory biomarkers in women. This proposal will utilize a well-characterized rodent model to elucidate the fundamental cellular/molecular mechanisms by which ovarian hormones, particularly estrogen (E2), modulate the inflammatory response to acute endoluminal vascular injury. Our preliminary studies have demonstrated extensive inflammatory cell infiltration and increased expression of a variety of proinflammatory mediators in carotid arteries of ovariectomized rats within hours after balloon injury. We have made the novel and provocative preliminary observation that E2 inhibits granulocyte and monocyte/macrophage infiltration, as well as proinflammatory mediator expression in injured arteries. The synthetic progestin medroxyprogesterone acetate (MPA) blocks this anti-inflammatory effect. We have also observed that E2 inhibits expression of chemokines known to be chemoattractant for leukocytes in vascular smooth muscle cells (VSMCs) in vitro. The proposed research, based on these exciting and provocative preliminary observations, as well as our extensive experience in studying ovarian hormone-induced modulation of the vascular injury response, will identify the inflammatory cell types whose activation/migration can be modulated by ovarian hormones and will define the signaling cascade by which these cells direct the response to endoluminal arterial injury in the presence and absence of ovarian hormones. Novel highly selective (subtype specific) and potent agonists and antagonists of estrogen receptors (ERalpha and ERbeta), RNA interference technology and microarray analyses will be used to provide a rigorous assessment of the functional role of anti-inflammatory mechanisms in mediating the vasoprotective effects of E2 in this model. Upon successful completion of the proposed research, the cellular/molecular mechanisms responsible for the anti-inflammatory effects of E2 on injured arteries and their inhibition by MPA will be elucidated and related to the extent of the injury response (i.e. neointima formation). These fundamental mechanistic studies will enhance our understanding of the pathobiology of vascular disease, particularly as it occurs in aging women, and will provide the basis for development of novel therapeutic strategies.

描述（由申请人提供）：炎症在许多形式的血管疾病的发病机制中起重要作用，并且已显示绝经期激素治疗可调节女性中炎症生物标志物的表达。该提案将利用一个良好的特征啮齿动物模型，阐明卵巢激素，特别是雌激素（E2），调节急性腔内血管损伤的炎症反应的基本细胞/分子机制。我们的初步研究表明，广泛的炎性细胞浸润和多种促炎介质在球囊损伤后数小时内的卵巢切除大鼠颈动脉的表达增加。我们已经进行了新颖的和挑衅性的初步观察，E2抑制粒细胞和单核细胞/巨噬细胞浸润，以及在受损动脉中的促炎介质的表达。合成的孕酮醋酸甲羟孕酮（MPA）阻断这种抗炎作用。我们还观察到，E2在体外抑制已知为血管平滑肌细胞（VSMCs）中白细胞的趋化因子的表达。基于这些令人兴奋和挑衅性的初步观察，以及我们在研究卵巢囊肿诱导的血管损伤反应调节方面的丰富经验，拟议的研究将确定其激活/迁移可由卵巢激素调节的炎性细胞类型，并将定义这些细胞在存在和不存在卵巢激素的情况下指导对腔内动脉损伤的反应的信号级联。新的高选择性（亚型特异性）和有效的激动剂和拮抗剂的雌激素受体（ER α和ER β），RNA干扰技术和微阵列分析将被用来提供一个严格的评估抗炎机制的功能作用，介导的血管保护作用的E2在这个模型中。在成功完成拟议的研究后，将阐明E2对损伤动脉的抗炎作用及其MPA抑制作用的细胞/分子机制，并与损伤反应（即新生内膜形成）的程度相关。这些基本的机制研究将提高我们对血管疾病的病理生物学的理解，特别是当它发生在老年女性时，并将为开发新的治疗策略提供基础。