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: 7943940
• 负责人: Serrine S Lau
• 金额: $ 47.21万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943940
• 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; early life exposure; 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.

项目名称：早期生命哮喘保护性暴露的蛋白质组学特征挑战领域：03生物标志物发现和验证挑战主题：新暴露评估方法的验证（03- es -101）项目总结越来越多的证据表明，环境暴露，特别是发生在生命早期关键发育窗口的环境暴露，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，一些纵向人口研究一致表明，早期生活甚至可能在产前接触某些家畜（例如，室内狗）与生命后期对哮喘和哮喘相关表型（过敏，湿疹）的强保护有关。这个阶段的挑战是阐明狗接触的保护作用的生物学机制，作为利用这些机制进行预防的一步。因此，该项目的总体目标是开始使用基于质谱的新方法来确定这些机制。我们的具体目标是识别和表征早期与狗接触的儿童的血浆或血清中的蛋白质组学特征，这些儿童在早期生活中有或没有接触过狗，并且在5-8岁时被诊断为哮喘或未被诊断为哮喘。我们试图验证的假设是：a)在暴露儿童的蛋白质组中可以检测到早期狗接触的特定特征；B)这些信号标记了环境信号靶向的分子，并与疾病发病机制有关，c)暴露和疾病状态的信号比较为识别受环境信号激活的分子途径提供了线索，这些途径参与赋予哮喘保护作用。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）方面的协同专业知识，以及来自婴儿免疫研究（IIS）的一组独特的样本和数据。这项在亚利桑那大学亚利桑那呼吸中心进行的哮喘和过敏的纵向研究，在出生时招募了大量健康儿童，并在8年后仍在跟踪他们，收集有关免疫参数、过敏致敏和肺功能的详细表型信息。与当前的应用程序相关，已经创建了一个库，用于存放从IIS儿童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提出的实验计划确定的生物标志物与环境暴露和/或哮喘疾病结果之间建立强大的相关性。质谱（MS）电离方法和仪器的最新发展使得蛋白质的快速、高通量分析和翻译后修饰的位点特异性鉴定成为可能。质谱是在有限数量的可用样品下测序肽和蛋白质的首选方法，针对低丰度的蛋白质和检测低率的重要修饰。这些分析能力将推动生物标志物发现、验证和实施的未来增长。亚利桑那大学（UA）将利用世界一流的蛋白质组学和生物统计学能力进行生物标志物的发现和开发。特别值得一提的是，2008年，基础和临床科学家开始了一项合作，重点是使用从定义明确的人类样本队列中提取的一小部分样本开发血清生物标志物，我们将利用这些样本探索出生前暴露于过敏原对哮喘发展的影响。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，因为它目前影响了包括美国在内的许多西方国家10-15%的人口，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原型复杂疾病的易感性的途径。此外，发现与保护性环境暴露相关的生物标志物的新方法的发展将很容易适用于多种其他条件，其中表型结果由环境和内源性因素之间的相互作用决定。因此，通过我们的项目制定的策略可能有助于将保护性暴露转化为有效的预防和/或治疗策略。一个关键的组成部分是，拟议的纵向设计将允许检查不仅来自多个个体的血浆样本，而且在不同时间从同一个人获得的样本。因此，我们的研究可能为蛋白质组随时间的稳定性以及个体内部和个体间体内变异的存在程度提供新的见解。