Integrative Genomics of Acute Asthma Control

急性哮喘控制的综合基因组学

基本信息

批准号：
10365951
负责人：
Joshua Millstein
金额：
$ 77.65万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-06 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365951
关键词：
Acute Air Pollution Allergens Allergic Amplifiers Asthma Attenuated Biological Markers CD14 gene Cell Surface Receptors Cell surface Cells Child Chronic Clinical Clinical Data Crohn&apos s disease Data Dendritic Cells Deterioration Endotoxins Environmental Exposure Environmental Risk Factor Europe Event Failure Future Gene Expression Gene Expression Profile Genetic Genomic approach Genomics Goals Grant Hospitalization Individual Individual Differences Inflammation Inflammatory Lead Measures Mediating Mediation Medical Care Costs Modeling Molecular Myeloid Cells North America Pathway interactions Patients Pattern Pattern recognition receptor Pharmaceutical Preparations Pharmacology Phenotype Plasma Play Pyroglyphidae Reporting Reproducibility Research Resolution Role Sampling Schools Severities Signal Pathway Symptoms T cell response TLR4 gene TNF gene Testing Therapeutic Time Virus Diseases Work adaptive immune response affection airway inflammation allergic airway inflammation antagonist asthma exacerbation asthma inhaler asthmatic asthmatic patient base cohort first-in-human genetic signature genetic variant individual variation inhibitor macrophage monocyte mouse model patient population peripheral blood potential biomarker pre-clinical prevent programs receptor single-cell RNA sequencing transcriptome sequencing treatment response young adult

项目摘要

The overarching hypothesis underpinning our research is that inter-individual differences in asthma control result from the interplay of genetic and environmental factors organized in discrete molecular networks. During the first grant cycle, we explored this hypothesis by defining the molecular determinants of asthma control in well characterized patient populations using integrative genomic approaches. Among our most notable observations was our discovery that asthmatics with suboptimal asthma control demonstrate a peripheral blood gene expression signature indicative of activation of the TREM1 signaling pathway. Triggering Receptor Expressed On Myeloid Cells 1 (TREM1) is a cell-surface receptor expressed on monocytes and macrophages that plays a critical role in modulating both the innate and adaptive immune response. We now hypothesize that the activation of TREM1 is a critical early molecular event in the worsening of asthma control, and that inhibition of this signaling pathway represents new and effective non-steroidal strategy for maintaining long- term asthma control. We will test these hypotheses in the following complementary Specific Aims: In Specific Aim 1 we will use both single cell and bulk RNA-sequencing to characterize the patterns of TREM1 expression and pathway activation in monocyte subtypes from 100 children and young adults with variable asthma control. Our goals are to define and classify monocyte subsets based on their TREM1 activation status; correlate monocyte-specific TREM1 activation signatures with asthma control; and assess whether these signatures can predict deterioration in asthma control and exacerbation. In Specific Aim 2 we will evaluate soluble TREM1 (sTREM1) as a potential biomarker of asthma control. sTREM1 is shed from cell surfaces and plasma sTREM1 levels correlate with clinical severity in several inflammatory conditions. We will measure sTREM1 plasma levels in samples from more than 2,500 asthmatics to determine (i) if sTREM1 can serve as a biomarker of asthma control and predict asthma exacerbation; (ii) if high sTREM1 levels define a specific clinical asthma subtype or responsiveness to specific asthma therapies; and (iii) if sTREM1 levels are determined by specific genetic or environmental exposures, and, if so, do they mediate correlations with asthma control? In Specific Aim 3, we will use an established mouse model of allergic airway inflammation to evaluate the therapeutic potential of inhibition of the TREM1 signaling pathway in the treatment of asthma. We anticipate that LR12 will demonstrate strong efficacy in these models, providing essential pre-clinical data to support future first-in- human trials of this compound in asthmatic patients.

我们研究的基础的总体假设是哮喘控制的个体间差异由离散分子网络中组织的遗传和环境因素的相互作用产生。期间第一个赠款周期，我们通过定义哮喘控制的分子决定因素来探讨了这一假设使用综合基因组方法表征良好的患者人群。在我们最著名的观察结果是我们发现具有次优哮喘控制的哮喘患者证明了外周血液基因表达特征指示了TREM1信号通路的激活。触发受体在髓样细胞1（trem1）上表达的是在单核细胞和巨噬细胞上表达的细胞表面受体这在调节先天和适应性免疫反应方面起着至关重要的作用。我们现在假设在哮喘控制恶化的情况下，trem1的激活是一个关键的早期分子事件，并且抑制此信号通路代表了维持长期的新的和有效的非甾体策略术语哮喘控制。我们将在以下互补特定目的中检验这些假设： AIM 1我们将同时使用单细胞和散装RNA测序来表征TREM1表达的模式来自100名儿童和年轻人哮喘控制的儿童和年轻人的单核细胞亚型的途径激活。我们的目标是根据其TREM1激活状态来定义和分类单核细胞子集；相关单核细胞特异性TREM1激活特征具有哮喘控制；并评估这些签名是否可以预测哮喘控制和恶化的恶化。在特定目标2中，我们将评估可溶性trem1 （Strem1）作为哮喘控制的潜在生物标志物。 streem1是从细胞表面和等离子体streem1脱落的在几种炎症条件下，水平与临床严重程度相关。我们将测量Strem1等离子体来自2500多种哮喘患者的样本中的水平以确定（i）是否可以用作生物标志物哮喘控制和预测哮喘加剧；（ii）如果较高的streem1水平定义了特定的临床哮喘亚型或对特定哮喘疗法的反应性；（iii）如果通过特异性确定streem1水平遗传或环境暴露，如果是的，它们是否介导了与哮喘控制的相关性？具体 AIM 3，我们将使用已建立的过敏气道炎症的鼠标模型来评估治疗性在治疗哮喘中抑制TREM1信号通路的潜力。我们预计LR12会在这些模型中表现出强大的功效该化合物在哮喘患者中的人体试验。