Sex differences in macrophage differentiation in allergic lung inflammation

过敏性肺部炎症巨噬细胞分化的性别差异

基本信息

批准号：
9100898
负责人：
NICOLA M HELLER
金额：
$ 40.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100898
关键词：
15 year old Adrenal Cortex Hormones Adult Agonist Allergic Allergic inflammation Androgen Receptor Androgens Animals Asthma Biology Bone Marrow Bronchoalveolar Lavage Fluid Cells Cessation of life Characteristics Data Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Exposure to Extrinsic asthma Female Fibrosis Gene Expression Genes Goals Gonadal Steroid Hormones Health Helminths Hormones Hospitalization Human Human Characteristics Immune Implant In Vitro Inflammatory Response Interleukin-13 Interleukin-4 Lung Lung Inflammation Mediating Modeling Molecular Molecular Target Mus Ovariectomy Pathogenesis Pathology Patients Pharmaceutical Preparations Phenotype Play Population Prevalence Pulmonary Inflammation Recruitment Activity Research Respiratory physiology Role STAT6 gene Severities Sex Characteristics Signal Transduction Signal Transduction Induction Signal Transduction Pathway Signaling Molecule Steroid Receptors Structure of parenchyma of lung Testing Time Translating Treatment Efficacy Woman Women&apos s Role Wound Healing asthmatic base cellular targeting cytokine differential expression human disease improved in vivo macrophage male men monocyte mouse model new therapeutic target novel peripheral blood personalized medicine receptor receptor expression response sex

15 year old Adrenal Cortex Hormones Adult Agonist Allergic Allergic inflammation Androgen Receptor Androgens Animals Asthma Biology Bone Marrow Bronchoalveolar Lavage Fluid Cells Cessation of life Characteristics Data Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Exposure to Extrinsic asthma Female Fibrosis Gene Expression Genes Goals Gonadal Steroid Hormones Health Helminths Hormones Hospitalization Human Human Characteristics Immune Implant In Vitro Inflammatory Response Interleukin-13 Interleukin-4 Lung Lung Inflammation Mediating Modeling Molecular Molecular Target Mus Ovariectomy Pathogenesis Pathology Patients Pharmaceutical Preparations Phenotype Play Population Prevalence Pulmonary Inflammation Recruitment Activity Research Respiratory physiology Role STAT6 gene Severities Sex Characteristics Signal Transduction Signal Transduction Induction Signal Transduction Pathway Signaling Molecule Steroid Receptors Structure of parenchyma of lung Testing Time Translating Treatment Efficacy Woman Women&apos s Role Wound Healing asthmatic base cellular targeting cytokine differential expression human disease improved in vivo macrophage male men monocyte mouse model new therapeutic target novel peripheral blood personalized medicine receptor receptor expression response sex

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项目摘要

DESCRIPTION (provided by applicant): Patients over 15 years old requiring hospitalization for asthma are up to three times more likely to be female than male. Women comprised 64% of the asthma-associated deaths in 2009. Mainstay asthma therapies are often ineffective in women. Animal studies recapitulate the human disease: the hallmark features of allergic lung inflammation are worse in female mice compared to male mice and estrogen (E2) worsens lung inflammation. The lungs of both female mice and humans with asthma have greater numbers of alternatively activated (or M2) macrophages, correlating with worse lung function in humans. The broad objective of this proposal is to understand the molecular basis of sex differences in macrophages and their contribution to pathogenesis in allergic lung inflammation. The Specific Aims are to determine intrinsic sex differences in M2 differentiation in macrophages from male and females and the role of sex hormones (E2, DHT) and their receptors in regulating these differences in vitro and in vivo. Based on our preliminary data, we hypothesize that (i) macrophages from females express characteristic M2 phenotypic genes in response to IL-4 more highly compared to male cells and (ii) that E2 promotes and androgens suppress IL-4-induced M2 differentiation. We will test these hypotheses by defining differences in IL-4 receptor expression, IL-4-activated signal transduction pathways and induction of M2 gene expression in different mouse and human macrophage populations in vitro. We will also determine the effect of E2 and DHT on M2 differentiation, monocyte recruitment and macrophage turnover in the lung in vivo using mouse models of allergic lung inflammation in hormone-treated animals. Understanding these sex differences will help uncover novel targets for therapy in asthmatic women and tailor more effective, personalized therapies for asthma and allergic inflammation based on the sex of the patient.

描述（由申请人提供）：15岁以上的患者需要住院治疗哮喘，女性的可能性是男性的三倍。妇女在2009年占哮喘相关死亡的64％。主要的哮喘疗法在女性中常常无效。动物研究概括了人类疾病：与雄性小鼠和雌激素（E2）相比，雌性小鼠过敏性肺部炎症的标志性特征更严重，肺部炎症恶化。雌性小鼠和人类哮喘的肺均具有更多的替代激活（或M2）巨噬细胞，与人类的肺功能较差有关。该提案的广泛目的是了解巨噬细胞中性别差异的分子基础及其对过敏性肺部炎症发病机理的贡献。具体的目的是确定男性和女性巨噬细胞中M2分化的内在性别差异，以及性激素（E2，DHT）的作用及其受体在体外和体内调节这些差异方面的受体。基于我们的初步数据，我们假设（i）女性的巨噬细胞表达特征性的M2表型基因对IL-4的响应，与雄性细胞相比，对IL-4的反应更高，并且（ii）E2促进和雄激素抑制IL-4诱导的M2分化。我们将通过定义IL-4受体表达，IL-4激活的信号转导途径的差异以及在体外不同小鼠和人类巨噬细胞种群中M2基因表达的诱导来检验这些假设。我们还将使用激素治疗的动物中过敏性肺部炎症的小鼠模型来确定E2和DHT对肺部肺部体内M2分化，单核细胞募集和巨噬细胞更新的影响。了解这些性别差异将有助于发现哮喘女性治疗的新颖靶标，并根据患者的性别量身定制更有效的个性化疗法对哮喘和过敏性炎症。