Gonadal hormones as mediators of sex and gender influences in asthma

项目摘要 microRNAs（miRNAs）是一类长度小于25个核苷酸的小分子非编码RNA，具有重要的调控作用 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 反应这些转录后调节因子通过直接的翻译抑制和/或 诱导靶mRNA降解。miRNA的异常表达与肿瘤的发生、发展和预后有关。 年轻人发生和加重肺部疾病，包括哮喘、COPD和肺癌 和老年人。然而，尽管在肺部疾病的发病率和严重程度方面存在已知的性别差异， 很少有研究调查了miRNAs在介导这种性别差异中的作用。这个的主要目标 一个研究miRNAs在男性和女性哮喘发展中所起的作用的项目， 导师实验室提供了屋尘螨暴露的小鼠模型。Silveyra博士之前的研究 在小鼠的实验室（PI）报告了性别差异和肺中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，我们假设性别特异性miRNA 表达介导哮喘期间激活的性别特异性免疫应答，通过调节肺 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中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miRNA签名，有助于哮喘 表型（目标3）。拟议的IRS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，以获得独立的研究资金。培训和指导将 包括与导师和她在印第安纳州大学布卢明顿的调查小组的会议，以及与 两个额外的教师顾问，正式的课程，和研讨会。课程将侧重于多组学方法 和个性化医疗，以建立对与设计相关的基本问题的理解， 行为、分析和数据解释。课程作业将辅以实验室培训 建立对肺部疾病病理生物学的理解的技术。这种指导与 和课程将装备候选人与必要的工具，创造一个有意义的，有效的， 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.