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; 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.

项目摘要 microRNA（miRNA）是一类小型非编码RNA，具有≤25个核苷酸，起着至关重要的调节作用 在广泛的细胞和生物学过程中，包括免疫调节，凋亡和炎症 回复。这些转录后调节剂通过直接翻译抑制和/或 诱导靶mRNA降解。异常miRNA表达与 肺部疾病的发育和加剧，包括年轻人的哮喘，COPD和肺癌 和较老的人群。然而，尽管肺部疾病的事件和严重程度有已知的性别分布，但 很少有研究研究miRNA在介导这种性别差异中的作用。这个主要目标 项目是通过使用一个 心理实验室中可用的房屋灰尘暴露的鼠标模型。 Silveyra博士的先前研究 小鼠的实验室（PI）报告了肺中循环性激素水平的性别差异和影响 对环境暴露的炎症反应。在这项研究中，我们假设该性别特定的miRNA 表达通过调节肺部调节在哮喘期间激活的性别特异性免疫反应 炎症基因表达。为了检验这一假设，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染色体完成和性腺激素哮喘表型 模型（目标1）。我们还将评估性恐怖对男性和女性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miRNA特征，导致哮喘 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 科学知识和沟通技巧，精通分子生理基准研究 技术并获得初步数据以获得独立的研究资金。培训和心理将 涉及与印第安纳大学布卢明顿大学的心理和调查团队会面，以及 另外两名教师顾问，正式的课程和半手。课程将重点放在多摩克的方法上 和个性化医学，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。课程将补充实验室的培训 建立对肺部疾病病理生物学的理解的技术。这种心理的结合 课程将使候选人为创建有意义，有效和 可持续研究计划。