Gender-based precision care for asthma

基于性别的哮喘精准护理

基本信息

批准号：
10225221
负责人：
Joe Zein
金额：
$ 10.04万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-07 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225221
关键词：
5q31 Adrenal Cortex Hormones Adult Affect Age American Area Asthma Award Biochemical Pathway Biological Body mass index Candidate Disease Gene Characteristics Child Childhood Asthma Cilia Clinic Clinical Clinical Research Data Data Set Databases Development Development Plans Dose Drug Targeting Education Endocrinology Environment Epidemiology Epithelial Cells Estradiol European Exhibits Female Foundations GTP-Binding Protein alpha Subunits, Gs Gender Genes Genetic Genetic Risk Genetic Transcription Genomics Glucocorticoids Glutamine Goals Gonadal Steroid Hormones Hormonal IRF1 gene Immunity Incidence Inhalation Interferons Isoleucine Knowledge Laboratories Life Cycle Stages Linear Regressions Longevity Menopause Mentors Mucociliary Clearance National Heart, Lung, and Blood Institute Natural History Outcome Participant Pathogenesis Pathway interactions Patient Care Patients Pharmaceutical Preparations Physicians Predisposition Prevalence Productivity Progesterone Proteins Puberty Pulmonary Function Test/Forced Expiratory Volume 1 Reporting Research Research Institute Research Proposals Respiratory physiology Risk Role Scientist Severities Sex Differences Single Nucleotide Polymorphism Subgroup Testing Testosterone Time Ubiquitin Variant Vocational Guidance Woman activating transcription factor 1 airway obstruction asthmatic base boys career career development cohort epidemiology study experience female sex hormone gender difference genetic association genetic epidemiology genetic variant genome wide association study genome-wide genomic locus girls improved innovation male men middle age patient oriented personalized care programs response risk variant sex success tiotropium bromide whole genome

项目摘要

ABSTRACT Asthma affects boys more than girls, but gender-switch occurs after puberty and asthma is more common in women than men. This research proposal investigates gender effect(s) on asthma severity. The long-term goal of our studies is to identify sex related differences in genetic risks and biological pathways of severe asthma. Our analyses of large databases reveal that severe asthma exhibits a bimodal peak in young boys and middle age women [1, 2], which pointes to sex hormones in mechanisms of asthma severity [1]. Preliminary data of sex hormone levels in participants with asthma from the Severe Asthma Research Program (SARP I&II; 2001- 2012) shows that men with both low progesterone and low testosterone and women with low testosterone and high estradiol have the most severe airflow limitation. Additionally, our genome-wide association analyses of single nucleotide polymorphism (SNP) x sex interaction and candidate gene analyses of European American adults with asthma in SARP I & II shows sex-specific genetic associations with percent predicted FEV1, a marker of severe asthma. Based on the findings, we hypothesize that risk of severe asthma is gender dependent due to variation in levels of male and/or female sex hormones over the lifecourse and the consequent interactions of sex hormones with asthma risk variants that result in a bimodal peak of severe asthma in boys and women. In aim 1, we will assess SNP × sex interactions across the whole genome using genome wide interaction study (GWIS). We will also use a candidate gene approach, which will determine SNP x sex interactions in previously described asthma severity gene loci, such as lung function and immunity pathway genes. In aim 2, we investigate the effect of variations in sex hormone levels on the risk for severe asthma differentially in males and females. Equally important and parallel to the research plan, the career development plan is constructed for didactic coursework, one-on-one education and career guidance from strong mentors and collaborators expert in asthma, endocrinology, and analytical genetics. This research will be performed in the laboratory of Dr. Erzurum, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by experts in genomics and biochemical pathways unique to asthma. The LRI offers the ideal intellectual and research environment for success. The proposed research is innovative and significant as it may lay the groundwork for the care of patients with severe asthma in a personalized, gender specific way. Altogether the award will provide the candidate the knowledge, hands-on experience, expertise and productivity to develop into an independent physician-scientist focused on patient-centered mechanistic research.

抽象的哮喘对男孩的影响大于女孩，但性别转换发生在青春期后，哮喘在以下人群中更常见该研究计划调查性别对哮喘严重程度的影响。我们的研究目的是确定严重哮喘的遗传风险和生物学途径中与性别相关的差异。我们对大型数据库的分析表明，严重哮喘在年轻男孩和中学中表现出双峰峰值年龄女性 [1, 2]，这表明性激素在哮喘严重程度的机制中 [1]。严重哮喘研究计划 (SARP I&II; 2001- 2012）表明，孕酮和睾酮水平均较低的男性以及睾酮水平和睾酮水平均较低的女性此外，我们的全基因组关联分析显示，高雌二醇具有最严重的气流限制。欧洲裔美国人的单核苷酸多态性 (SNP) x 性别相互作用和候选基因分析 SARP I 和 II 中患有哮喘的成人显示，性别特异性遗传与预测的 FEV1 百分比存在关联，根据研究结果，我们发现严重哮喘的风险是性别。由于生命过程中男性和/或女性性激素水平的变化而依赖性激素与哮喘风险变异的后续相互作用，导致严重哮喘的双峰峰值在目标 1 中，我们将使用整个基因组评估 SNP × 性别相互作用。我们还将使用候选基因方法来确定 SNP。 x 先前描述的哮喘严重程度基因位点中的性别相互作用，例如肺功能和免疫力在目标 2 中，我们研究了性激素水平的变化对重症风险的影响。哮喘在男性和女性中的差异与研究计划同等重要且平行。发展计划是为教学课程、一对一教育和职业指导而制定的这项研究将由哮喘、内分泌学和分析遗传学领域的专家提供强有力的指导和合作。在克利夫兰诊所勒纳研究所 (LRI) Erzurum 博士的实验室中进行，并将由哮喘特有的基因组学和生化途径专家提供的建议提供了理想的选择。所提出的研究具有创新性和意义，因为它具有成功的智力和研究环境。可能为以个性化、针对性别的方式治疗严重哮喘患者奠定基础。总而言之，该奖项将为候选人提供知识、实践经验、专业知识和生产力发展成为一名独立的医师科学家，专注于以患者为中心的机制研究。