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

哮喘中 ILC2 的迁移和信号传导：男性和女性差异

• 批准号: 10045501
• 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/10045501
• 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; 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; 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 - 以下申请旨在启动 Kristi J. 的研究生涯。 沃伦 (Warren)，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，师从 [罗伯特·潘恩 (Robert Paine)] 三、医学博士；在过去 20 多年里，他是一位受人尊敬、由 VA 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，此后完成了博士后培训，重点关注 仅限于肺免疫科学。环境——【犹他大学毗邻 乔治·E·瓦伦退伍军人医疗中心和研究医院，临床和科学关系已建立 成立是为了完成拟议的研究。]研究环境是合作性的、支持性的， 与具有相似兴趣的其他科学家互动的大量机会。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 VA 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 在退伍军人群体中确诊。哮喘的发病率存在性别差异，严重哮喘的发病率更高 成年女性退伍军人比男性更常见，并且与哮喘相关的死亡女性多于男性。在 一般来说，卵巢激素被认为会导致疾病恶化，而睾酮则可以保护 对抗哮喘。最近，第 2 组先天淋巴细胞 (ILC2) 引起了人们的注意，它被证明可以 接触过敏原后会产生大量促哮喘细胞因子（IL-5 和 IL-13）。我们 观察到激活的 ILC2 存在性别差异，因此从雌性过敏原治疗的小鼠中分离出肺 ILC2 与男性相比，男性产生更高的 IL-5、IL-13 和 2 型趋化因子 CCL17 和 CCL22。在这个 研究提案我们将使用经过缓释激素颗粒处理的去腺雌性小鼠来 评估雌激素、孕激素和[睾酮]对实验性哮喘的独立作用。那里 目标 1 的两个目标是：(1) 定义肺介导的 ILC2 募集和定位方面的性别差异 通过趋化因子受体 CCR4 和 CRTH2 及其同源趋化因子 CCL17/22 和 PGD2， 分别（subaim 1a）。 (2) Subaim 1b 将专门定义激活的肺-ILC2 的趋化因子表达 接触过敏原后。因为 ILC2 非常接近气道上皮和其他驻留细胞 免疫细胞，这些研究旨在分离性激素对免疫细胞总趋化因子环境的影响 来自激活的 ILC2 的肺。这些研究将全面定义基于性激素的 在过敏原挑战期间对肺部产生的趋化因子环境的影响。目标 2 将调查性别 IL-33 介导的 ILC2 激活的差异，ILC2 通过 MyD88- 驱动 IL-5 和 IL-13 的产生 依赖的信号通路。 IL-33-MyD88 信号传导此前尚未在 ILC2 中进行过评估，也未在 ILC2 中进行过评估。 性激素对 IL-33 信号传导的影响已经确定。在子目标 2a 中，我们将通过以下方式检查该机制： 哪种性激素会改变小鼠中 IL-33 诱导的 ILC2 激活，在 subaim 2b 中，我们将从中分离出 ILC2 健康和哮喘患者、女性和男性退伍军人捐献者的血液，将我们的发现转化为退伍军人 人口。目标 3 将类似地检查小鼠和小鼠中雄性和雌性 γC 依赖性信号传导机制。 人类ILC2。我们对人类 ILC2 的初步数据表明，女性 ILC2 的增殖效率高于女性 ILC2。 当用 IL-2 和 IL-7（γC 依赖性细胞因子）刺激时，雄性 ILC2 会发生变化。因为 γC 是 ILC2 存活所必需的 和增殖，我们将评估 JAK-STAT 和 PI3K-TOR 激活与性激素的相互作用 IL-2 和 IL-7 刺激后。该项目的范围是新颖的信号机制 定义，从而产生个性化的治疗策略，旨在更有效地限制哮喘负担 高度易感的退伍军人群体。此外，该项目将有效启动独立的 候选人在退伍军人管理局医学研究界的科学生涯。