Gonadal hormones as mediators of sex and gender influences in asthma

项目总结 MicroRNAs(MiRNAs)是一类含有≤25个核苷酸的非编码小RNA，起着重要的调节作用 在广泛的细胞和生物过程中，包括免疫调节、细胞凋亡和炎症 回应。这些转录后调控因子通过直接翻译抑制和/或 诱导靶基因的降解。MiRNA的异常表达与这两种疾病有关 在年轻人中发展和加重肺部疾病，包括哮喘、慢性阻塞性肺病和肺癌 和老年人口。然而，尽管在肺部疾病的发病率和严重性方面存在已知的性别差异， 很少有研究调查miRNAs在调节这种性别差异中的作用。这样做的主要目标是 该项目旨在研究miRNAs在男性和女性哮喘发病中所起的作用，方法是使用 在导师的实验室中提供了暴露于室内尘螨的小鼠模型。西尔维拉博士之前的研究 实验室(PI)报道了小鼠的性别差异和肺部循环性激素水平的影响 对环境暴露的炎症反应。因此，在这项研究中，我们假设特定性别的miRNA 表达通过调节肺组织来介导性特异性免疫反应在哮喘期间被激活 炎性基因表达。为了验证这一假设，我们将评估不同性别miRNA表达的差异。 应用四种核心基因型鼠的染色体补体和性激素哮喘表型 模式(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，我们将确定雌激素受体诱导的与哮喘有关的miRNA信号。 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台研究 技术，并获得初步数据，以获得独立研究资金。培训和指导将 与导师和她在印第安纳大学布鲁明顿分校的调查团队会面，以及与 另外两名教师导师，正式的课程作业和研讨会。课程将侧重于多种组学方法 和个性化医学建立了对设计相关基本问题的理解， 进行、分析和数据解释。课程作业将辅之以实验室培训。 建立对肺部疾病的病理生物学的理解的技术。这种指导的结合 课程工作将为候选人提供必要的工具，以创建有意义、有效和 可持续研究计划。

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.