Sex-specific Regulation of Acute Inflammation and Resolution

急性炎症和消退的性别特异性调节

基本信息

批准号：
8230358
负责人：
KARSTEN GRONERT
金额：
$ 37.68万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230358
关键词：
Accounting Acute Address Affect Agonist Animal Model Arachidonate 15-Lipoxygenase Autacoids Autoimmune Diseases B-Lymphocytes Cells Chronic Chronic Disease Clinic Clinical Clinical Trials Complex Cornea Corneal Ulcer Cutaneous Data Analyses Disease Dry Eye Syndromes Employee Strikes Enzymes Epithelial Epithelial Cells Estrogen Receptors Estrogens Etiology Event Excision Exhibits Eye Female G-Protein-Coupled Receptors Gene Targeting Genetic Human Immune System Diseases Immune response Immune system Impaired wound healing Impairment In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Knowledge LOX gene Lead Leukocytes Link Lipids Lymphocyte Mediating Mediator of activation protein Menopause Modeling Mus Neutrophil Infiltration Nuclear Receptors Opportunistic Infections Pathogenesis Pathologic Neovascularization Pathway interactions Patients Pharmacology Phenotype Population Pregnancy Receptor Signaling Recruitment Activity Regulation Resolution Retina Role Safety Signal Transduction Pathway Sjogren&apos s Syndrome Structure-Activity Relationship Testing Time Tissues Woman Wound Healing corneal epithelium experience eye dryness insight interest lipid mediator lipoxin A4 macrophage male mimetics mouse model novel ocular surface prospective prostatitis receptor research study response sex wound

项目摘要

DESCRIPTION (provided by applicant): There is a great interest and unresolved paradox regarding the complex role of estrogen in immune and inflammatory responses. Sex-specific differences and estrogen's role in ocular inflammatory diseases are not well understood, even though Dry Eye Syndromes primarily affect women. Receptors for estrogens, ER1 and ER2, are expressed in leukocytes and in every ocular tissue. Acute healthy inflammation depends on the early recruitment of neutrophils, their tightly controlled activation and subsequent removal by recruited macrophages. Dysregulation of this essential response likely represent the early event that triggers inflammatory and chronic diseases. The lipid mediator lipoxin A4 (LXA4) has been identified as key mediator of inflammatory resolution and regulators of leukocyte function. The cornea highly expresses a key enzyme for LXA4 formation, 15-lipoxygenase (15-LOX), and its G-protein coupled receptor ALX. Genetic disruption of the 15-LOX/LXA4 circuit leads to dysregulated inflammation, wound healing and pathological angiogenesis in the cornea. Preliminary studies demonstrate that female mice consistently exhibit delayed epithelial wound closure. A prospective clinical trial in 120 patients with corneal ulcers, documents for the first time, that epithelial wounds healed twice as slow in female patients. The female phenotype of delayed wound healing can be recapitulated by treating male mice with topical estrogen and in in vitro experiments with corneal epithelial cells. More importantly, ER1 and ER2 specific agonists differentially regulated inflammation, epithelial wound healing and the expression and activity of the intrinsic 15-LOX/LXA4 circuit. These findings correlate with lipidomic analysis from a dry eye model that demonstrates striking impairment in corneal 15-LOX activity in female mice. Estrogen's selective regulation of this intrinsic lipid circuit may provide novel insights into the etiology or pathogenesis of sex-specific ocular surface inflammatory diseases, which will be tested in three specific aims: I. Characterize sex-specific differences in the intrinsic 15-LOX and LXA4 circuit during acute and reoccurring epithelial injury and inflammation in the cornea. II. Elucidate the role of the estrogen receptors (ER1 and ER2) in the regulation of corneal epithelial and leukocyte wound healing function and define receptor specific regulation of the 15-LOX and LXA4 circuit in these cells. III. Delineate the role ER1 and ER2 in the corneal pathogenesis of dry eye in mice and define the protective role of the intrinsic 15-LOX and LXA4 circuit. Result from this study will address critical gaps of knowledge regarding the role of estrogen and its receptors in acute inflammatory/reparative responses in the eye and will define for the first time sex-specific (estrogen) regulation of intrinsic lipid circuits that are critical for inflammatory resolution. Our knowledge of structure function relationships, receptors and signal transduction pathways for LXA4 and related mimetics is relatively advanced and efficacy/safety in animal models have been established. Hence, results from this study could rapidly bring novel treatment options for ocular surface inflammatory diseases to the clinic. PUBLIC HEALTH RELEVANCE: This study will address critical gaps of knowledge regarding the role of estrogen and its receptors in acute inflammatory/reparative responses in the eye and will define for the first time sex-specific (estrogen) regulation of intrinsic lipid circuits that are critical for inflammatory resolution. Due to the advanced pharmacology and clearly defined targets of endogenous protective lipid mediators, results from this study could rapidly bring novel treatment options for ocular surface inflammatory diseases to the clinic.

描述（由申请人提供）：关于雌激素在免疫和炎症反应中的复杂作用，存在极大的兴趣和未解决的悖论。性别特异性的差异和雌激素在眼部炎症性疾病中的作用尚不清楚，即使干眼综合症主要影响女性。雌激素ER1和ER2的受体在白细胞和每个眼组织中表达。急性健康的炎症取决于中性粒细胞的早期募集，其严格控制的激活以及随后被招募的巨噬细胞清除。这种基本反应的失调可能代表了触发炎症和慢性疾病的早期事件。脂质介质Lipoxin A4（LXA4）已被确定为炎症分辨率和白细胞功能调节剂的关键介体。角膜高度表达了LXA4形成，15-脂氧合酶（15-lox）及其G蛋白偶联受体ALX的关键酶。 15-LOX/LXA4电路的遗传破坏会导致角膜中的炎症，伤口愈合和病理血管生成失调。初步研究表明，雌性小鼠始终表现出延迟的上皮伤口闭合。一项针对120例角膜溃疡患者的前瞻性临床试验，第一次记录，上皮伤口在女性患者中恢复了两倍。可以通过用局部雌激素和角膜上皮细胞进行体外实验来概括延迟伤口愈合的女性表型。更重要的是，ER1和ER2特定的激动剂差异调节的炎症，上皮伤口愈合以及内在的15-LOX/LXA4电路的表达和活性。这些发现与干眼症模型的脂质分析分析相关，该模型证明了在雌性小鼠中角膜15-LOX活性中的惊人障碍。雌激素对这种固有的脂质电路的选择性调节可能会提供有关性别特异性眼表炎性疾病的病因或发病机制的新颖见解，这将在三个特定的目的中进行测试：I。在急性和重新核心术中的固有15-lox和LXA4电路中表征性别特异性差异，cornea in cornea in Cornea and incornea in Cornea in Cornea in Cornea ins in Cornea ins in Cornea ins in Cornea ins in the Cornea ins in the Cornea ins ins in Cornea。 ii。阐明雌激素受体（ER1和ER2）在角膜上皮和白细胞伤口愈合功能的调节中的作用，并定义了这些细胞中15-LOX和LXA4电路的受体特异性调节。 iii。描述小鼠干眼的角膜发病机理中的作用ER1和ER2，并定义了内在的15-LOX和LXA4电路的保护作用。这项研究的结果将解决有关雌激素及其受体在眼睛中急性炎症/修复反应中的作用的关键差距，并将首次定义性别特异性（雌激素）调节内在脂质电路对炎症分辨率至关重要的固有脂质电路。我们对LXA4和相关模拟物的结构功能关系，受体和信号转导途径的了解相对先进，并且已经建立了动物模型的功效/安全性。因此，这项研究的结果可能会迅速将眼部表面炎症性疾病的新型治疗选择带到诊所。公共卫生相关性：这项研究将解决有关雌激素及其受体在眼睛中急性炎症/修复反应中的作用的关键差距，并将首次定义性别特异性（雌激素）的内在脂质电路，这对于炎症分辨率至关重要。由于先进的药理学和内源性保护性脂质介质的明确定义靶标，这项研究的结果可能会迅速将眼部表面炎症性疾病的新型治疗选择带到诊所。