Gene Expression Profiling in Asthma Severity: CHI3L1 Genotypes and Serum YKL-40

描述(由申请人提供)：在本申请中，我们建议根据与几丁质酶-3-样-1(CHI3L1)/YKL-40相关的基因表达谱来表征哮喘的严重程度，我们最近确定了几丁质酶-3-样-1/YKL-40在哮喘发病机制中的重要分子。在这些研究中，我们发现编码几丁质酶蛋白家族新分子YKL-40的CHI3L1基因的一个功能突变与哮喘、支气管高反应性和肺功能有关。此外，我们还发现这种功能突变与血清YKL-40水平密切相关，而血清YKL-40水平又与哮喘严重程度呈正相关，与肺功能和气道壁厚度(气道重塑)呈负相关。总之，这些发现表明CHI3L1/YKL-40是导致哮喘的原因途径的一部分，并且YKL-40的表达增加在哮喘严重程度中起作用。这些研究还表明，循环蛋白水平可以反映肺中蛋白质的表达，循环中的基因表达可以用于哮喘的表型和识别与哮喘严重程度相关的基因。基于这些发现和额外的初步数据，我们假设循环中存在反映肺中与CHI3L1/YKL-40基因/表型和哮喘严重程度相关的生物现象的基因表达谱。沿着这些思路，我们产生了以下特定的假设，形成了这一提议的基础：1)循环和肺的基因表达谱将区分与CHI3L1/YKL-40基因型/表型相关的肺和/或免疫系统特异性谱。 这些图谱将反映哮喘严重程度(AIM 1)；2)基因表达谱随时间的波动将识别CHI3L1/YKL-40基因型/表型的特异性图谱，并将反映哮喘严重程度(AIM 2)；3)在全基因组水平上将基因和蛋白质表达与遗传变异相关联将识别与CHI3L1/YKL-40和哮喘严重度(AIM 3)相关的新分子和多态。本申请中描述的研究结果将对哮喘严重程度如何分类以及CHI3L1/YKL-40如何与哮喘严重程度相关产生显著影响。这些结果还将产生重要的数据集，将循环中的基因表达与诱导痰中的基因表达相关联，因为它与哮喘严重程度有关，这些特征如何相互关联，以及它们如何随时间变化以及与CHI3L1/YKL-40和哮喘严重程度的关系。最终，这些研究将通过确定与CHI3L1/YKL-40和哮喘严重程度相关的表达模式，得出有助于选择新的哮喘疗法和抗CHI3L1/YKL-40药物的受试者以及确定哮喘预后的结果，从而促进基因图谱在哮喘临床上的应用。

DESCRIPTION (provided by applicant): We propose in this application to characterize asthma severity based on the gene expression profiles in relation to chitinase-3-like-1(CHI3L1)/YKL-40, a molecule we have recently determined to be important in asthma pathogenesis. In these studies, we found that a functional mutation in the CHI3L1 gene encoding YKL-40, a novel molecule in the chitinase protein family, is associated with asthma, bronchial hyperresponsiveness, and lung function. In addition, we determined that this functional mutation correlates strongly with serum YKL-40 levels, which in turn correlate positively with asthma severity and negatively with lung function and airway wall thickness (airway remodeling). Together, these discoveries suggest that CHI3L1/YKL-40 is part of the causal pathway that leads to asthma and that increased expression of YKL-40 plays a role in asthma severity. These studies also demonstrated that levels of circulating proteins can be reflective of protein expression in the lung and that gene expression in the circulation can be used to phenotype asthma and identify genes related to asthma severity. Based on these findings and additional preliminary data, we hypothesize that there are gene expression profiles in the circulation that reflect biologic phenomena in the lung associated with CHI3L1/YKL-40 genotypes/phenotypes and asthma severity. Along these lines, we have generated the following specific hypotheses that form the basis of this proposal: 1) Gene expression profiling of the circulation and the lung will discriminate lung and/or immune system specific profiles associated with CHI3L1/YKL-40 genotypes/phenotypes. These profiles will reflect asthma severity (AIM 1); 2) Fluctuations in gene expression profiles over time will identify profiles specific for CHI3L1/YKL-40 genotypes/phenotypes and will reflect asthma severity (AIM 2); 3) Correlating gene and protein expression with genetic variation at the genome-wide level will identify novel molecules and polymorphisms associated with CHI3L1/YKL-40 and asthma severity (AIM 3). The results of the studies described in this application will have marked impact on how asthma severity is classified and the how CHI3L1/YKL-40 is associated with asthma severity. The results will also generate important datasets correlating gene expression in the circulation with gene expression in induced sputum as it relates asthma severity, how these profiles correlate, and how they change over time and in relation to CHI3L1/YKL-40 and asthma severity. Ultimately, these studies will yield results that will facilitate the use of gene profiling in the asthma clinic by identifying expression patterns associated with CHI3L1/YKL-40 and asthma severity that may be useful in selecting subjects for novel asthma therapeutics and anti-CHI3L1/YKL-40 agents and in determining asthma prognosis.