Proteomic signatures of an early life asthma-protective exposure

生命早期哮喘保护性暴露的蛋白质组学特征

• 批准号: 7830029
• 负责人: Serrine S Lau
• 金额: $ 46.67万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7830029
• 关键词: Adult; Affect; Age; Allergens; Allergic; Area; Arizona; Asthma; Biological; Biological Markers; Biology; Biometry; Birth; Canis familiaris; Child; Childhood; Chronic Disease; Clinical; Complex; Cues; Data; Development; Diagnosis; Disease; Disease Outcome; Dissection; Domestic Animals; Eczema; Endogenous Factors; Enrollment; Environmental Exposure; Epidemiology; Exposure to; Extrinsic asthma; Future; Goals; Growth; Health; Housing; Human; Hypersensitivity; Immune; Immunology; Individual; Infant; Life; Light; Longitudinal Studies; Mass Spectrum Analysis; Methodology; Methods; Modification; Molecular; Outcome; Pathogenesis; Pathway interactions; Phenotype; Plasma; Population; Population Study; Post-Translational Protein Processing; Predisposition; Preventive; Proteins; Proteome; Proteomics; Public Health; Quality of life; Respiratory Center; Respiratory physiology; Sampling; Scientist; Serum; Signal Transduction; Site; Societies; Staging; Testing; Therapeutic; Time; Translating; United States; Universities; Validation; Variant; airborne allergen; airway inflammation; base; cohort; high throughput analysis; in vivo; insight; instrumentation; ionization technique; longitudinal design; microbial; novel; novel strategies; prenatal; prenatal exposure; protective effect; protein aminoacid sequence; public health relevance

DESCRIPTION (provided by applicant): Project title: Proteomic signatures of an early life asthma-protective exposure Challenge Area: 03 Biomarker discovery and validation Challenge Topic: Validation of new exposure assessment methodologies (03-ES-101) Project Summary Mounting evidence suggests that environmental exposures, particularly when occurring at a critical developmental window in early life, can profoundly affect the phenotypes associated with complex diseases such as allergic asthma. In particular, several longitudinal population studies have consistently shown that early life and possibly even prenatal exposure to certain domestic animals (e.g., indoor dogs) is associated with strong protection against asthma and asthma-related phenotypes (allergy, eczema) later in life. The challenge at this stage is to elucidate the biological mechanisms responsible for the protective effects of dog exposure as a step towards leveraging these mechanisms for preventive purposes. The overall goal of this Project therefore is to begin identifying these mechanisms using new mass spectrometry-based methodologies. Our specific aim is to identify and characterize proteomic signatures of early life dog exposure in the plasma or serum of children who have or have not been exposed to dogs in early life, and who were or were not diagnosed with asthma by age 5-8 yrs. The hypotheses we seek to test are: a) specific signatures of early dog exposure are detectable in the proteome of the exposed children; b) these signatures mark molecules targeted by environmental signals and are related to disease pathogenesis, and c) a comparison of signatures by exposure and disease status provide clues for the identification of molecular pathways activated by environmental cues and which are involved in conferring protection from asthma. In order to achieve our goals, we will rely on our synergistic expertise in proteomics (Lau), epidemiology (Halonen), allergy biology and immunology (Vercelli), and biostatistics (Billheimer) as well as on a unique set of samples and data from the Infant Immune Study (IIS). This longitudinal study of asthma and allergy, conducted at the Arizona Respiratory Center, University of Arizona, enrolled at birth a large population of healthy children and is still following them 8 years later, gathering detailed phenotypic information about immunological parameters, allergic sensitization and lung function. Relevant to the current application, a bank has been created that houses plasma and/or serum samples obtained from IIS children at multiple time points. This wealth of samples and information will allow us to establish robust correlations between the biomarkers identified through the proposed experimental plan and environmental exposure and/or the disease outcome of asthma. Recent developments in mass spectrometry (MS) ionization methods and instrumentation now make possible the rapid, high throughput analysis of proteins and site-specific identification of post-translational modifications. MS is the method of choice for sequencing peptides and proteins with limited amounts of available sample, targeting low abundance proteins and detecting low rates of important modifications. These analytical capabilities will drive the future growth of biomarker discovery, validation, and implementation. The University of Arizona (UA) will leverage world-class competencies in proteomics and biostatistics for biomarker discovery and development. In particular, a collaborative effort of basic and clinical scientists was initiated in 2008 focusing on the development of serum biomarkers using a small set of samples from a well-defined cohort of human samples, with which we will explore the effect of pre-birth exposure of allergens in asthma development. The potential impact of our project is both broad and significant. Asthma imposes a heavy burden on society because it currently affects 10-15% of the population in many western nations, including the United States, and it is the most common chronic disease in childhood. Our results will shed light on the pathways harnessed by a common environmental exposure to modify susceptibility to this prototypic complex disease. Moreover, the development of novel approaches to the discovery of biomarkers related to protective environmental exposures would be readily applicable to multiple other conditions in which phenotypic outcomes are determined by interactions between environmental and endogenous factors. The strategies developed through our project may therefore help in translating protective exposures into effective preventive and/or therapeutic strategies. A key component is that the proposed longitudinal design will allow for the examination not only of plasma samples from multiple individuals, but also of samples obtained at different times from the same individuals. Our study is therefore likely to provide novel insights into the proteome's stability over time, and the extent to which intra- and inter-individual in vivo variations both exist. Public Health Relevance: Asthma continues to be a major health problem in the United States and worldwide. Asthma affects the health and quality of life of millions of children and adults. It has been suggested that exposure to microbial products in early life may have both systemic (decreased aeroallergen sensitization) and local (decreased airway inflammation) effects that may protect against the development of asthma. The goal of this Project is to initiate a dissection of these mechanisms by new mass spectrometry-based methodologies to identify and characterize proteomic signatures of early life dog exposure in the plasma of children who have or have not been exposed to dogs in early life, and who were, or were not, diagnosed with asthma by age 5-8 yrs.

描述(由申请人提供)：项目名称：早期哮喘的蛋白质组学签名-保护性暴露挑战领域：03 Biomarker发现和验证挑战主题：新暴露评估方法的验证(03-ES-101)项目摘要越来越多的证据表明，环境暴露，特别是当发生在早期生命的关键发育窗口时，可以深刻影响与过敏性哮喘等复杂疾病相关的表型。特别是，几项纵向人口研究一直表明，早期生活，甚至可能在出生前接触某些家畜(例如，室内狗)与对哮喘和晚年哮喘相关表型(过敏、湿疹)的强大保护有关。现阶段的挑战是阐明造成犬只暴露的保护作用的生物学机制，以此作为利用这些机制进行预防的一个步骤。因此，该项目的总体目标是开始使用新的基于质谱学的方法来确定这些机制。我们的具体目标是鉴定和表征早期接触狗的儿童血浆或血清中狗暴露的蛋白质组特征，这些儿童在早期生活中已经或没有接触过狗，并且在5-8岁之前被诊断为或没有被诊断为哮喘。我们试图测试的假设是：a)在暴露的儿童的蛋白质组中可以检测到早期暴露于狗的特定特征；b)这些特征标记了环境信号所针对的分子，与疾病发病机制有关；以及c)暴露和疾病状态的特征比较为识别由环境线索激活的分子通路提供了线索，这些分子参与了对哮喘的保护。为了实现我们的目标，我们将依靠我们在蛋白质组学(LAU)、流行病学(Halonen)、过敏生物学和免疫学(Vercelli)和生物统计学(Billheimer)以及来自婴儿免疫研究(IIS)的一组独特的样本和数据方面的协同专业知识。这项关于哮喘和过敏的纵向研究在亚利桑那大学亚利桑那呼吸中心进行，在出生时招募了大量健康儿童，并在8年后仍在跟踪他们，收集有关免疫学参数、过敏反应和肺功能的详细表型信息。与当前的应用相关的是，已经建立了一个银行，存储从IIS儿童那里在多个时间点获得的血浆和/或血清样本。这些丰富的样本和信息将使我们能够在通过拟议的实验计划确定的生物标记物与环境暴露和/或哮喘疾病结局之间建立牢固的相关性。质谱仪(MS)电离方法和仪器的最新发展使蛋白质的快速、高通量分析和翻译后修饰的特定位点识别成为可能。MS是在可用样本数量有限的情况下对多肽和蛋白质进行测序的首选方法，目标是低丰度蛋白质并检测低比率的重要修饰。这些分析能力将推动生物标记物发现、验证和实施的未来增长。亚利桑那大学(UA)将利用蛋白质组学和生物统计学方面的世界级能力来发现和开发生物标记物。特别是，基础和临床科学家于2008年启动了一项合作努力，重点是使用从明确定义的人类样本中提取的一小组样本来开发血清生物标记物，我们将利用这些样本来探索出生前接触变应原在哮喘发生中的作用。我们项目的潜在影响既广泛又重大。哮喘给社会带来了沉重的负担，因为在包括美国在内的许多西方国家，目前有10%-15%的人口患有哮喘，而且它是儿童时期最常见的慢性病。我们的结果将阐明通过共同的环境暴露来改变对这种典型复杂疾病的易感性的途径。此外，开发新的方法来发现与保护性环境暴露有关的生物标记物将很容易适用于多种其他条件，在这些条件下，表型结果由环境和内生因素之间的相互作用决定。因此，通过我们的项目制定的战略可能有助于将保护性暴露转化为有效的预防和/或治疗战略。一个关键的组成部分是，拟议的纵向设计将不仅允许检查来自多个个人的血浆样本，而且还允许检查在不同时间从相同个人获得的样本。因此，我们的研究很可能为蛋白质组随时间的稳定性以及体内个体内和个体间变异的存在程度提供新的见解。 公共卫生相关性：哮喘仍然是美国和世界范围内的一个主要健康问题。哮喘影响着数以百万计的儿童和成人的健康和生活质量。有人提出，在生命早期接触微生物产品可能具有全身性(减少空气变应原敏感度)和局部(减少呼吸道炎症)效应，可能会预防哮喘的发展。该项目的目标是通过新的基于质谱学的方法对这些机制进行剖析，以识别和表征早期接触狗的儿童血浆中的蛋白质组特征，这些儿童在早期接触过或没有接触过狗，在5-8岁之前被诊断为或没有被诊断为哮喘。