Genomic Signatures for Idiopathic Interstitial Pneumonia

描述(由申请人提供)： 该项目的总体目标是结合特发性间质性肺炎(IIP)患者的遗传学和基因组研究结果，开发和验证表型锚定分子特征，以完善这组复杂疾病的诊断标准。传统上根据客观的临床特征(病史、生理学、放射学和病理学)来定义IIP。这种方法将看似同质性的疾病分开，包括急性间质性肺炎(AIP)、淋巴细胞性肺炎(LIP)和隐源性机化性肺炎(COP)，但特发性肺纤维化(IPF)、非特异性间质性肺炎(NSIP)和一组不属于特定类别的IIP在重叠模式方面仍然是不同的，往往无法诊断。大量证据支持这一概念，即根据目前的定义，这些后几类IIP在表现形式、结果和治疗反应方面仍包括一种不同的表型。甚至那些看似同质的实体实际上也有可能包括混合群体。例如，临床上出现的AIP实际上可能代表了IPF的急性加重，到目前为止，IPF经历了一个非常缓慢的、临床上未被认识到的过程，形成了一个快速的爆炸期。虽然间质性肺炎的生物学特征正在显现，但这些典型的间质性肺炎的分子特征(或特征)尚未与这些纤维性间质性肺炎的传统临床诊断特征相结合。在IIP中，我们实验室和其他实验室的基因表达研究表明，这种疾病的某些形式(IPF和家族性IIP)但不是所有(NSIP)形式都有独特的分子特征。鉴于IIP亚型的重叠分类，以及多个基因在这类疾病的发展中发挥作用的可能性，这一点也就不足为奇了。例如，大约10%的IIP患者由于表面活性蛋白C或端粒酶基因突变而患上疾病，推测导致了两个不同的分子特征。我们最近在82个家系中进行了一项连锁研究，其中=2个成员可能/确定了IIP，并在第10、11和12号染色体上发现了可能包含导致IIP家族性形式的基因的区域，同样可能导致了不同的分子特征。迫切的挑战是在IIP患者中结合遗传和基因组方法来定义IIP的分子表型，这些表型可以用来区分这组复杂疾病的临床方面。为了应对这一挑战，我们假设IIP转录组受到遗传变异的影响，结合临床特征，这些分子特征可用于完善这组复杂疾病的诊断标准。为了验证这一假设，我们将把全基因组RNA表达的结果与遗传学研究中的感兴趣区域/基因结合起来，开发和验证IIP及其亚型的表型锚定分子签名。(摘要结束)

DESCRIPTION (provided by applicant): The overall goal of this project is to combine genetic and genomic findings in patients with idiopathic interstitial pneumonia (IIP) to develop and validate phenotypically anchored molecular signatures that serve to refine the diagnostic criteria for this group of complex diseases. IIP has traditionally been defined by objective clinical characteristics (history, physiology, radiography, and pathology). This approach splits out diseases that appear to be homogeneous including acute interstitial pneumonia (AIP), lymphocytic pneumonia (LIP), and cryptogenic organizing pneumonia (COP) but idiopathic pulmonary fibrosis (IPF), non specific interstitial pneumonia (NSIP), and a group of IIPs that do not fit a specific category remain heterogeneous in terms of overlapping patterns that often defies diagnostic labeling. Substantial evidence supports the concept that these latter categories of IIP, as currently defined, still comprise a heterogeneous phenotype in terms of pattern of presentation, outcome, and response to therapy. It is also possible that even those entities that appear to be homogeneous may in fact comprise mixed groups. For example, what appears clinically to be AIP may, in fact, represent an acute exacerbation of IPF that has hitherto experienced a very indolent and therefore clinically unrecognized course that has developed a rapid explosive phase. While the biological features of IIP are emerging, these molecular attributes (or signatures) that are prototypical of IIP have not yet been integrated with the traditional clinical diagnostic characteristics for these fibrosing interstitial pneumonias. In IIP, gene expression studies from our lab and others have demonstrated unique molecular signatures for some (IPF and familial forms of IIP) but not all (NSIP) forms of this disease. Given the overlapping classification of IIP subtypes and the likelihood that multiple genes play a role in the development of this group of diseases, this is not at all surprising. For instance, about 10% of patients with IIP develop disease due to mutations in either surfactant protein C or telomerase genes, presumably resulting in two distinct molecular signatures. We have recently performed a linkage study in 82 families with = 2 members with probable/definite IIP and have identified regions on chromosomes 10, 11, and 12 that likely contain genes contributing to familial forms of IIP, again presumably resulting in distinct molecular signatures. The compelling challenge is to combine genetic and genomic approaches in patients with IIP to define molecular phenotypes of IIP that can be used to distinguish the clinical aspects of this group of complex diseases. To address this challenge, we hypothesize that the IIP transcriptome is influenced by genetic variants and that, in combination with clinical characteristics, these molecular signatures can be used to refine the diagnostic criteria for this group of complex diseases. To test this hypothesis, we will combine the results of genome-wide RNA expression with regions/genes of interest from genetic studies to develop and validate phenotypically anchored molecular signatures for IIP and its subtypes. (End of Abstract)