Migration and signaling in ILC2 in asthma: Male and female differences

哮喘中 ILC2 的迁移和信号转导：男性和女性差异

• 批准号: 10292918
• 负责人: Kristi J Warren
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292918
• 关键词: Acute; Adult; Airway Disease; Allergens; Allergic; Allergic inflammation; Asthma; Attention; B-Lymphocytes; Blood; CC chemokine receptor 4; CCL11 gene; CCL17 gene; CCL22 gene; CCL3 gene; Caring; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Communities; Complex; Data; Dendritic Cells; Diagnosis; Disease; Doctor of Philosophy; Environment; Estrogens; Event; Extrinsic asthma; Feedback; Female; Functional disorder; Funding; Future; General Population; Goals; Gonadal Steroid Hormones; Health; Healthcare; Healthcare Systems; Hormones; Hospitals; Human; Hypersensitivity; IL7 gene; Immune; Immunobiology; Immunologics; Incidence; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interleukin 2 Receptor Gamma; Interleukin-13; Interleukin-2; Interleukin-5; Iowa; Link; Lung; Lymphoid Cell; Mediating; Mediator of activation protein; Medical; Medical Research; Medical center; Mentorship; Mission; Mus; Nebraska; Ovarian; Ovarian hormone; Pathology; Pathway interactions; Pilot Projects; Play; Population; Population Growth; Production; Progesterone; Proliferating; Prostaglandin D2; Reporting; Research; Research Personnel; Research Proposals; Respiratory Signs and Symptoms; Role; Science; Scientist; Severity of illness; Sex Differences; Signal Pathway; Signal Transduction; Source; Symptoms; Testosterone; Therapeutic Studies; Translating; United States Department of Veterans Affairs; Universities; Utah; Veterans; Woman; Work; airway epithelium; airway hyperresponsiveness; allergic airway disease; asthmatic; asthmatic airway; base; biological sex; career; chemokine; chemokine receptor; chronic respiratory disease; cytokine; design; eosinophil; human data; in vivo; individualized medicine; interest; macrophage; male; men; migration; military veteran; mouse allergy; novel; personalized therapeutic; post-doctoral training; recruit; respiratory; respiratory challenge; response; sex; sex disparity

Project Summary: Candidate—The following application is intended to initiate the research career of Kristi J. Warren, PhD within the VA Nebraska Western Iowa Health Care System under the mentorship of [Robert Paine III, MD; a well-respected, VA-funded pulmonary researcher and clinician for the past 20+ years]. Dr. Warren received her PhD in Immunobiology in 2012 and has since completed her postdoctoral training focused exclusively in the pulmonary immunologic sciences. Environment—[The University of Utah is adjacent to the George E. Wahlen VA Medical Center and research hospital where clinical and scientific relationships have been established to complete the proposed studies.] The research environment is collegial and supportive with a multitude of opportunities for interaction with other scientists with similar interests. Specifically, Dr. Warren will have every opportunity to discuss/present her work for crucial feedback and direction from senior VA researchers. Research—In recent years, asthma and other chronic respiratory illnesses are increasingly diagnosed in the Veteran population. There is a sex-based disparity in asthma such that severe asthma is more prevalent in adult female Veterans than males, and more asthma-linked deaths occur in women than men. In general, ovarian hormones are thought to contribute to disease exacerbation, whereas testosterone protects against asthma. Recently, attention was drawn to the group 2 innate lymphoid cells (ILC2), which are shown to produce large amounts of asthma-promoting cytokines (IL-5 and IL-13) following allergen exposure. We observed a sex difference in activated ILC2 such that lung ILC2 isolated from female allergen-treated mice produced higher IL-5, IL-13, and the type 2 chemokines, CCL17 and CCL22, in comparison to males. In this research proposal we will use gonadectomized female mice treated with slow-release hormone pellets to evaluate the independent effect of estrogen, progesterone, and [testosterone] in experimental asthma. There are two goals for Aim 1: (1) define sex differences in recruitment and localization of ILC2 in the lung mediated through the chemokine receptors CCR4 and CRTH2 and their cognate chemokines, CCL17/22 and PGD2, respectively (subaim 1a). (2) Subaim 1b will define the chemokine expression specifically by activated lung-ILC2 following allergen exposure. Because ILC2 are in close proximity to the airway epithelium and other resident immune cells, these studies are designed to separate the sex hormone effect on the total chemokine milieu of the lung from that of the activated ILC2. These studies will comprehensively define the sex hormone-based effects on the chemokine milieu developed in the lung during allergen challenge. Aim 2 will investigate sex differences in IL-33-mediated activation of ILC2, which drives the production of IL-5 and IL-13 through a MyD88- dependent signaling pathway. IL-33-MyD88 signaling has not been previously evaluated in ILC2, nor has the effect of sex hormones on IL-33 signaling been established. In subaim 2a we will examine the mechanism by which sex hormones alter IL-33-induced activation of ILC2 in mice, and in subaim 2b we will isolate ILC2 from the blood of healthy and asthmatic, female and male Veteran donors to translate our findings to Veteran population. Aim 3 will similarly examine male and female γC-dependent signaling mechanisms in mouse and human ILC2. Our preliminary data from human ILC2 suggests that female ILC2 proliferate more efficiently than male ILC2 when stimulated with IL-2 and IL-7, γC-dependent cytokines. Because γC is required for ILC2 survival and proliferation, we will evaluate JAK-STAT and PI3K-TOR activation for interactions with the sex hormones following IL-2 and IL-7 stimulation. The scope of this project is such that novel signaling mechanisms can be defined, leading to personalized therapeutic strategies designed to more effectively limit the asthma burden in the highly susceptible Veteran population. Furthermore, this project will effectively launch the independent scientific career of the candidate within the VA medical-research community.

项目摘要：候选人-以下申请是为了启动克里斯蒂J。 沃伦，弗吉尼亚州内布拉斯加州西部爱荷华州医疗保健系统博士，在罗伯特·佩恩的指导下 医学博士，过去20多年来一直受人尊敬、退伍军人事务部资助的肺部研究人员和临床医生]。沃伦博士 2012年获得免疫生物学博士学位，此后完成了专注于 专门研究肺部免疫学。环境-[犹他大学毗邻 乔治·E·沃伦退伍军人医学中心和研究医院，临床和科学关系一直在那里 为完成拟议的研究而设立。]研究环境是合作者和支持性的， 有很多机会与其他有相似兴趣的科学家互动。具体来说，沃伦博士将 有机会讨论/展示她的工作，以获得高级退伍军人管理局的重要反馈和指导 研究人员。研究-近年来，哮喘和其他慢性呼吸道疾病越来越多 在退伍军人中确诊。哮喘患者中存在性别差异，因此严重哮喘患者 在成年女性退伍军人中比男性更常见，与哮喘相关的死亡在女性中比男性更多。在……里面 一般来说，卵巢激素被认为是导致疾病恶化的因素，而睾丸素则起到保护作用 治疗哮喘。最近，第2组先天淋巴样细胞(ILC2)引起了人们的注意，它们被证明是 过敏原暴露后会产生大量促进哮喘的细胞因子(IL-5和IL-13)。我们 观察到激活的ILC2的性别差异，以至于从雌性变应原处理的小鼠中分离出肺ILC2 与雄性相比，产生更高的IL-5、IL-13和2型趋化因子CCL17和CCL22。在这 研究建议我们将使用去性腺的雌性小鼠，用缓释激素颗粒治疗 评价雌激素、孕激素和[睾酮]在实验性哮喘中的独立作用。那里 目标1的两个目标是：(1)确定ILC2在肺中的招募和定位的性别差异 通过趋化因子受体CCR4和CRTH2及其同源趋化因子CCL17/22和PGD2， (次级目标1a)。(2)Subaim 1b将通过激活肺-ILC2特异性地定义趋化因子的表达 在接触了过敏原之后。因为ILC2非常接近呼吸道上皮和其他居住者 免疫细胞，这些研究旨在分离性激素对总趋化因子环境的影响 从激活的ILC2的肺中分离出来。这些研究将全面定义基于性激素的 变应原激发对肺内趋化因子环境的影响。目标2将调查性行为 IL-33介导的ILC2激活的差异，通过MyD88驱动IL-5和IL-13的产生 依赖的信号通路。IL-33-MyD88信令之前没有在ILC2中进行过评估，也没有 性激素对IL-33信号转导的影响已经确定。在次级目标2a中，我们将通过以下方式检查该机制 在小鼠中，哪些性激素改变了IL-33诱导的ILC2的激活，在SubAim 2b中，我们将从 健康和哮喘患者的血液，女性和男性退伍军人捐赠者将我们的发现翻译给退伍军人 人口。目标3将类似地研究雄性和雌性γC依赖的信号机制在小鼠和 人类ILC2。我们来自人类ILC2的初步数据表明，女性ILC2的增殖效率高于 男性ILC2在IL-2和IL-7的刺激下，γC依赖细胞因子。因为γC是ILC2生存所必需的 和增殖，我们将评估JAK-STAT和PI3K-TOR的激活与性激素的相互作用 IL-2和IL-7刺激后。该项目的范围是，新的信令机制可以 明确，导致个性化的治疗策略，旨在更有效地限制哮喘负担 高度敏感的退伍军人群体。此外，该项目将有效地启动独立的 候选人在退伍军人医学研究社区内的科学生涯。