Transcriptomic and Pharmacogenetic Asthma Endotypes in Minority Children

少数民族儿童哮喘内型的转录组学和药物遗传学

基本信息

批准号：
9493041
负责人：
Esteban Gonzalez Burchard
金额：
$ 6.01万
依托单位：
NATIONAL JEWISH HEALTH
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：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9493041
关键词：
Adrenal Cortex Hormones Affect African American Albuterol Asthma Biological Markers Blood Breathing Bronchoscopy Cell Culture Techniques Cells Child Childhood Asthma Chromosome Mapping Clinical Collaborations Communities Complex Computer Analysis DNA Data Death Rate Disease Environment Epithelial Epithelial Cells Exhibits Functional disorder Gene Expression Gene Expression Profiling Genetic Genetic Determinism Genetic Markers Genetic Screening Genetic Transcription Genomics Goals Health Policy Heterogeneity Human In Vitro Infection Interleukin-13 Laboratories Latino Lead Measures Medical Methods Modeling Molecular Molecular Profiling Morbidity - disease rate Nose Pathogenesis Pathology Patients Pharmaceutical Preparations Pharmacogenetics Population Public Health Publications Puerto Rican RNA Recurrence Research Resources Respiratory Signs and Symptoms Respiratory physiology Rhinovirus Risk Sampling Severities Subgroup Testing Therapeutic airway epithelium airway inflammation airway obstruction analytical method asthmatic clinical practice cytokine design differential expression disease phenotype ethnic difference ethnic diversity experience genome sequencing genome wide association study high risk minimally invasive minority children mortality novel peripheral blood personalized medicine racial and ethnic response success synergism targeted treatment trait transcriptome transcriptome sequencing transcriptomics whole genome

Adrenal Cortex Hormones Affect African American Albuterol Asthma Biological Markers Blood Breathing Bronchoscopy Cell Culture Techniques Cells Child Childhood Asthma Chromosome Mapping Clinical Collaborations Communities Complex Computer Analysis DNA Data Death Rate Disease Environment Epithelial Epithelial Cells Exhibits Functional disorder Gene Expression Gene Expression Profiling Genetic Genetic Determinism Genetic Markers Genetic Screening Genetic Transcription Genomics Goals Health Policy Heterogeneity Human In Vitro Infection Interleukin-13 Laboratories Latino Lead Measures Medical Methods Modeling Molecular Molecular Profiling Morbidity - disease rate Nose Pathogenesis Pathology Patients Pharmaceutical Preparations Pharmacogenetics Population Public Health Publications Puerto Rican RNA Recurrence Research Resources Respiratory Signs and Symptoms Respiratory physiology Rhinovirus Risk Sampling Severities Subgroup Testing Therapeutic airway epithelium airway inflammation airway obstruction analytical method asthmatic clinical practice cytokine design differential expression disease phenotype ethnic difference ethnic diversity experience genome sequencing genome wide association study high risk minimally invasive minority children mortality novel peripheral blood personalized medicine racial and ethnic response success synergism targeted treatment trait transcriptome transcriptome sequencing transcriptomics whole genome

展开

项目摘要

PROJECT SUMMARY Asthma affects 5% of the world population. In the U.S., asthma death rates are four-fold higher in Latinos and African Americans compared to Whites. Childhood asthma is a complex disease historically defined by partially overlapping clinical features. However, the heterogeneity observed in clinical disease and airway pathology suggests that the standard definition of asthma is composed of multiple clinical subgroups each with a distinct pathogenesis (i.e. endotypes). Gene expression profiling of bronchial airway brushings identified the type 2- high asthma endotype, defined by excessive airway inflammation driven by type 2 cytokines. We found that the type 2-high asthma endotype can be identified by gene expression profiling of minimally invasive nasal airway epithelium brushings. We also found high nasal expression of the type 2 cytokine, IL-13, was associated with higher risk of asthma attacks among Puerto Ricans, who have the highest asthma morbidity and mortality in the U.S. The populations with the highest asthma morbidity also have the poorest response to the most common asthma medication, albuterol. We hypothesize that specific molecular airway endotypes will define children with severe asthma and poor drug response and that these endotypes will have a strong genetic basis. To investigate this hypothesis the following aims are proposed: (1) Determine the expression endotypes of childhood asthma that underlie poor albuterol drug response and severe disease, using minimally invasive samples. Molecular endotyping with be performed by computational analysis of whole transcriptome sequencing data generated from 745 asthmatic and healthy children. Correlates of airway endotypes will be identified using peripheral blood gene expression. (2) Determine how IL-13 modifies airway cell responses to albuterol and HRV infection, and the genetic control of these responses. A powerful in vitro airway epithelial model will be used to determine if type 2 inflammation of the airway epithelium modifies transcriptional response to albuterol (most common asthma medication) and human rhinovirus (HRV) infection (most common trigger of asthma attacks). (3) Determine the genetic basis of and validate poor drug response and severe asthma endotypes in ethnically diverse children. We will perform the first genetic screen of type 2-high and other asthma endotypes. We will examine data from 4,379 minority children with asthma to determine how asthma endotypes influence response to albuterol and risk for severe asthma. Our goal is to understand the genetic basis of racial/ethnic differences in asthma severity and lung function. Results from this proposal will inform public health policy and clinical practice and aide in the mechanistic understanding of asthma severity (morbidity), which may lead to more targeted therapies. Data generated from our proposal will become a valuable resource for the medical and scientific communities.

项目摘要哮喘影响着5％的世界人口。在美国，拉丁美洲人的哮喘死亡率高四倍与白人相比，非洲裔美国人。儿童哮喘是一种复杂的疾病，从历史上部分定义重叠的临床特征。但是，在临床疾病和气道病理学中观察到的异质性表明哮喘的标准定义由多个临床亚组组成发病机理（即内型）。支气管气道刷子的基因表达分析确定了2型 - 高哮喘内型，由2型细胞因子驱动的气道炎症过多定义。我们发现可以通过微创鼻气道的基因表达分析来识别2型高哮喘内型上皮刷子。我们还发现2型细胞因子IL-13的高鼻表达与波多黎各人之间哮喘发作的风险较高，他们的哮喘发病率和死亡率最高美国哮喘发病率最高的人群对最多的反应也最差常见的哮喘药物，Albuterol。我们假设特定的分子气道内型将定义严重哮喘和药物反应不佳的儿童，这些内型将具有强大的遗传基础。为了研究这一假设，提出了以下目的：（1）确定表达式内型使用微创的童年哮喘是贫民窟药物反应和严重疾病的基础样品。通过整个转录组的计算分析来进行分子内测试从745个哮喘和健康儿童产生的测序数据。气道内型的关联将是使用外周血基因表达鉴定。（2）确定IL-13如何修改气道电池的响应 Albuterol和HRV感染，以及这些反应的遗传控制。强大的体外气道上皮模型将用于确定气道上皮的2型炎症是否会修饰转录对沙丁醇（最常见的哮喘药物）和人类鼻病毒（HRV）感染的反应（最常见的哮喘攻击的触发）。（3）确定药物反应不良和严重的遗传基础和验证种族多元化儿童的哮喘内型。我们将执行第2型2型的遗传屏幕，其他哮喘内型。我们将检查来自4,379名哮喘少数族裔儿童的数据，以确定如何哮喘内型会影响对白化醇的反应和严重哮喘的风险。我们的目标是了解哮喘严重程度和肺功能的种族/种族差异的遗传基础。该提议的结果将为公共卫生政策和临床实践提供信息，以及对哮喘严重程度的机械理解的助手（发病率），这可能导致更具靶向疗法。从我们的提案中产生的数据将成为医学和科学社区的宝贵资源。