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The role of ovarian hormones on allergen-mediatedd innate immune airway responses

卵巢激素对过敏原介导的先天免疫气道反应的作用

基本信息

批准号：
9211287
负责人：
Dawn C Newcomb
金额：
$ 22.12万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211287
关键词：
Affect Allergens Alternaria Antigens Asthma Automobile Driving B-Lymphocytes Basic Science Bone Marrow CD4 Positive T Lymphocytes Cell Proliferation Cell Surface Receptors Cell surface Cells Child Data Dendritic Cells Enzyme-Linked Immunosorbent Assay Estradiol Exposure to Extrinsic asthma Female Flow Cytometry Foundations Future GATA3 gene Gender Goals Gonadal Steroid Hormones Harvest Histocytochemistry Hormones Immune Immune response Inbred BALB C Mice Infiltration Innate Immune Response Interleukin-13 Interleukin-5 Life Liquid substance Lung Lymphoid Cell Mediating Menopause Metaplasia Mucous body substance Mus Ovarian hormone Pathogenesis Pathway interactions Patients Peptide Hydrolases Periodic acid Schiff stain method Phase Plethysmography Prevalence Production Progesterone Protein Secretion Protocols documentation Puberty Research Role Sex Characteristics Staining method Stains Stimulus Strategic Planning Surface T-Lymphocyte TSLP gene Testing Testosterone Time United States National Institutes of Health Woman Women&apos s Health adaptive immune response airway hyperresponsiveness airway inflammation allergic airway inflammation base boys cytokine eosinophil fungus gender disparity girls mRNA Expression macrophage male men microbial middle age operation protein expression public health relevance receptor response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Asthma prevalence is greater in boys than girls, but around puberty there is a shift in asthma prevalence, and at mid-life women are about two times more likely than men to have asthma. This suggests a role for sex hormones in asthma pathogenesis; however the mechanisms remain unknown. Group 2 innate lymphoid cells (ILC2) are important in driving the initial phase of allergic airway inflammation that is associated with asthma. ILC2 are activated by IL-33, TSLP, and IL-25 which are upregulated in response to airway allergens, including Alternaria alternata. Upon stimulation, ILC2 have increased expression of the transcription factors GATA3 and RORα and produce IL-5 and IL-13. IL-5 and IL-13 increase the infiltration of eosinophils, airway hyperresponsiveness (AHR), and mucus production, all hallmarks of asthma. Our preliminary data showed IL- 33-stimulated ILC2 from female mice had significantly increased IL-5 and IL-13 protein expression compared to ILC2 from male mice. Therefore, we hypothesize that the ovarian hormones, 17beta-estradiol (17β-E2) and progesterone (P4), increase ILC2-induced airway inflammation. In Aim 1 we will determine the mechanisms by which sex hormones increase IL-5 and IL-13 production from ILC2. Sham-operated female and male mice, ovariectomized female mice, and orchidectomized male mice will be administered pellets containing vehicle, 17β-E2, P4, and/or testosterone. ILCs will be harvested from the bone marrow and lungs of these mice and stimulated with IL-33 ex vivo. IL-5 and IL-13 protein expression, RORα and GATA3 mRNA expression, and surface expression of ST2, a component of the IL-33 receptor, will then be determined in ILC2. In Aim 2, we will determine the role of ovarian hormones on Alternaria extract (Alt Ex)-induced innate immune-mediated airway inflammation. WT BALB/c female, male, ovariectomized, and orchidectomized mice will be challenged with Alt Ex for 4 days to initiate an innate immune response. We will then determine ILC2 cytokine expression, airway inflammation, AHR, and mucus production. This proposal will delineate a mechanism(s) by which sex hormones regulate ILC2, and it may identify potential therapeutic targets for patients, in particular women, with asthma.