Gonadal hormones as mediators of sex and gender influences in asthma

性腺激素作为性和性别影响哮喘的介质

• 批准号: 10580911
• 负责人: Patricia Silveyra
• 金额: $ 17.47万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580911
• 关键词: Apoptosis; Asthma; Biological; Biological Process; Cell physiology; Chronic Obstructive Pulmonary Disease; Communication; Data; Data Analyses; Development; Environmental Exposure; Epigenetic Process; Estrogen Receptors; Faculty; Female; Four Core Genotypes; Frequencies; Funding; Future; Gender; Gene Expression; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Immune response; Incidence; Indiana; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Lead; Lung; Lung diseases; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mentors; MicroRNAs; Molecular; Mus; Nucleotides; Older Population; Phenotype; Physiology; Play; Ploidies; Pulmonary Pathology; Pyroglyphidae; Reporting; Research; Research Technics; Role; Severities; Sex Chromosomes; Sex Differences; Techniques; Testing; Training; Translational Repression; Universities; Untranslated RNA; asthma exacerbation; design; immunoregulation; mRNA Transcript Degradation; male; meetings; mouse model; multiple omics; personalized medicine; personalized therapeutic; programs; sex; sex disparity; skills; tool

PROJECT SUMMARY MicroRNAs (miRNAs) are a class of small noncoding RNAs with ≤25 nucleotides that play a vital regulatory role in a wide range of cellular and biological processes, including immune regulation, apoptosis and inflammatory response. These posttranscriptional regulators fine-tune gene expression via direct translational inhibition and/or induction of target mRNA degradation. Abnormal miRNA expression has been associated with both the development and exacerbation of pulmonary disease, including asthma, COPD, and lung cancer among young and older populations. Yet, in spite of the known sex disparities in the incidence and severity of lung diseases, few studies have investigated the role of miRNAs in mediating such sex differences. The primary goal of this project is to investigate the role played by miRNAs in asthma development in males and females, by using a mouse model of house dust mite exposure available in the mentor’s laboratory. Prior studies from Dr. Silveyra’s laboratory (PI) in mice have reported sex differences and influences of circulating sex hormone levels in the lung inflammatory response to environmental exposures. Thus, in this study, we hypothesize that sex-specific miRNA expression mediates sex-specific immune responses activated during asthma, via modulation of pulmonary inflammatory gene expression. To test this hypothesis, we will assess differences in miRNA expression in sex chromosome complement and gonadal hormone asthma phenotypes using the four core genotypes mouse model (Aim 1). We will also evaluate the impact of sex hormones on miRNA expression in male and female lungs (Aim 2). Finally, we will identify estrogen receptor-induced miRNA signatures that contribute to asthma phenotypes (Aim 3). The training plan of the proposed IRS diversity supplement will enable the candidate to gain scientific knowledge and communication skills, become proficient in molecular physiology bench research techniques, and obtain preliminary data to acquire independent research funding. Training and mentoring will involve meetings with the mentor and her investigative team at Indiana University Bloomington, as well as with two additional faculty advisors, formal coursework, and seminars. Courses will focus on multi-omics approaches and personalized medicine to establish an understanding of the fundamental issues related to the design, conduct, analysis, and data interpretation. Coursework will be supplemented with training in laboratory techniques to establish an understanding of the pathobiology of lung disorders. This combination of mentoring and coursework will equip the candidate with the tools necessary to create a meaningful, effective, and sustainable research program.

项目概要 MicroRNA（miRNA）是一类≤25个核苷酸的小非编码RNA，发挥着重要的调节作用 广泛的细胞和生物过程，包括免疫调节、细胞凋亡和炎症 回复。这些转录后调节因子通过直接翻译抑制和/或 诱导靶标 mRNA 降解。异常 miRNA 表达与以下两种因素有关： 年轻人中肺部疾病的发展和恶化，包括哮喘、慢性阻塞性肺病和肺癌 和老年人口。然而，尽管肺部疾病的发病率和严重程度存在已知的性别差异， 很少有研究调查 miRNA 在调节这种性别差异中的作用。本次活动的首要目标 该项目旨在通过使用 导师实验室提供了暴露于屋尘螨的小鼠模型。 Silveyra 博士之前的研究 小鼠实验室（PI）报告了性别差异以及肺部循环性激素水平的影响 对环境暴露的炎症反应。因此，在本研究中，我们假设性别特异性 miRNA 表达通过调节肺功能介导哮喘期间激活的性别特异性免疫反应 炎症基因表达。为了验证这一假设，我们将评估性别中 miRNA 表达的差异 使用四种核心基因型小鼠的染色体补体和性腺激素哮喘表型 模型（目标 1）。我们还将评估性激素对男性和女性 miRNA 表达的影响 肺（目标 2）。最后，我们将鉴定雌激素受体诱导的导致哮喘的 miRNA 特征 表型（目标 3）。拟议的国税局多样性补充的培训计划将使候选人能够获得 科学知识和沟通能力，精通分子生理学实验室研究 技术，并获得初步数据以获得独立研究经费。培训和指导将 包括与导师及其在印第安纳大学伯明顿分校的调查团队以及与 两名额外的教师顾问、正式课程和研讨会。课程将重点关注多组学方法 和个性化医疗，以建立对与设计相关的基本问题的理解， 进行、分析和数据解释。课程作业将辅以实验室培训 技术来建立对肺部疾病病理学的理解。这种辅导的结合 课程作业将为候选人提供必要的工具，以创造有意义的、有效的和 可持续研究计划。