Genomic Signatures for Idiopathic Interstitial Pneumonia

描述（由申请人提供）： 该项目的总体目标是将特发性间质性肺炎（IIP）患者的遗传学和基因组发现联合收割机，以开发和验证表型锚定的分子标记，用于完善这组复杂疾病的诊断标准。传统上，IIP由客观临床特征（病史、生理学、放射学和病理学）定义。这种方法分离出似乎是同质的疾病，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）和一组不符合特定类别的IIP在重叠模式方面仍然是异质的，这些模式通常无法诊断标签。大量证据支持这一概念，即目前定义的后几类IIP在表现模式、结局和治疗反应方面仍包含异质性表型。还有可能的是，即使那些看起来是同类的实体，实际上也可能包括混合群体。例如，临床上表现为AIP的疾病实际上可能代表IPF的急性加重，迄今为止经历了一个非常缓慢的过程，因此临床上未被识别，已经发展为快速爆发期。虽然IIP的生物学特征正在出现，但作为IIP原型的这些分子属性（或特征）尚未与这些纤维化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已经证明了某些（IPF和家族性IIP）但不是所有（NSIP）形式的独特分子特征。考虑到IIP亚型的重叠分类以及多个基因在这组疾病的发展中发挥作用的可能性，这一点也不奇怪。例如，约10%的IIP患者由于表面活性蛋白C或端粒酶基因突变而发生疾病，可能导致两种不同的分子特征。我们最近进行了连锁研究，在82个家庭= 2个成员可能/明确的IIP，并确定了区域上的染色体10，11和12，可能含有基因有助于家族形式的IIP，再次推测导致不同的分子特征。目前最大的挑战是将联合收割机的遗传学和基因组学方法结合起来，对IIP患者进行研究，以确定可用于区分这组复杂疾病临床特征的IIP分子表型。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，并且结合临床特征，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，我们将联合收割机将全基因组RNA表达的结果与来自遗传研究的感兴趣区域/基因相结合，以开发和验证IIP及其亚型的表型锚定分子特征。(End摘要）

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)