1/2 Prospective tReatment EffiCacy in IPF uSlng genOtype for Nac Selection (PRECISIONS) trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases study

摘要 尽管特发性肺纤维化是最常见和最致命的间质性肺病（ILD）， (IPF)诊断和治疗仍然具有挑战性。IPF的诊断过程依赖于主观 临床数据的解释，而目前的抗纤维化治疗采用“一种尺寸适合所有”的范例。 我们团队的成员一直站在开发“组学”方法的最前沿， ILD的预后。重要的是，我们确定了第一个药物基因组学相互作用，表明IPF患者 而TOLLIP rs3750920 T/T基因型则明显受益于NAC。我们迫切需要分子生物学 定义IPF的分类，从而允许基于精确度的管理。我们的长期目标是 ILD诊疗进入“精准医疗时代”。我们采用高度创新的方法 与肺纤维化基金会（PFF）临床护理网络（CCN）和登记处合作。这群 招募了提供了大量基线表型和纵向结局数据的ILD患者， 生物样本，并已同意重新联系，以供未来研究。我们的总体目标是 有效地在IPF中进行一项新的、基于精确基因型的试验，同时利用CCN及其独特的 采集生物标本，以从分子水平表征各种ILD并识别IPF的遗传变异 风险为了实现我们基于精确度的ILD管理目标，我们将完成三个互补的具体 目标。在目标1中，我们将确定NAC是否是IPF患者的有效治疗方法，其特征是精确性 基因型方法与PFF合作，我们将通过TOLLIP T/T识别PFF注册受试者 开始随机化200例IPF患者，然后在相同的临床研究中心招募新受试者， 以双盲方式接受NAC或安慰剂。这项研究，“IPF的前瞻性治疗效果 使用基因型进行Nac选择（PRECISIONS）”试验，将记录创新的“精确” 基因型特异性研究设计的耐受性良好和廉价的治疗。在目标2中，我们将区分IPF 使用血液转录组学和蛋白质组学的无偏组合从非IPF ILD中获得。我们建议 进行RNA-seq和蛋白质组学，以表征整个PFF上的基因表达和蛋白质生物标志物 登记队列。我们将定义区分IPF和非IPF ILD的“特征”。我们的公正方法 到“组学特征”将被整合，以揭示“组学风险评分， 以及对治疗的反应在目标3中，我们将确定在IPF风险中发挥作用的遗传变异。我们将 对整个PFF队列进行全基因组测序，以检测IPF的新遗传关联， ILD风险。有了足够的把握度，我们将评估常见和罕见/罕见变异， 种族匹配的未患病病例，以及ILD队列之间的病例，以满足我们的目标。这将建立 这是同类数据库中最大的一个，并为所有“组学”数据建立数量性状基因座。我们提出的结果 这些实验将使ILD管理，特别是IPF治疗进入精准医学时代。

ABSTRACT Despite being the most frequent and deadly of the interstitial lung diseases (ILD), Idiopathic Pulmonary Fibrosis (IPF) remains challenging to diagnose and treat. The diagnostic process for IPF relies on subjective interpretations of clinical data while current antifibrotic therapies employ a “one size fits all” paradigm. Members of our team have been at the forefront of developing `omics approaches to diagnose and define prognosis in ILDs. Importantly, we identified the first pharmacogenomic interaction suggesting that IPF patients with TOLLIP rs3750920 T/T genotype strongly benefited from NAC. There is a critical need for molecular classifications that define IPF, thus allowing precision-based management. Our long-term goals are to move ILD diagnosis and therapy into the “era of precision medicine.” In a highly innovative approach we have partnered with the Pulmonary Fibrosis Foundation (PFF) Clinical Care Network (CCN) and Registry. This group has recruited ILD patients who have provided extensive baseline phenotypic and longitudinal outcome data, biological samples and have consented to be re-contacted for future research. Our overall objective is to efficiently conduct a novel, precision genotype-based trial in IPF while leveraging the CCN and its unique biospecimen collection to characterize a broad range of ILDs molecularly and identify genetic variants of IPF risk. To address our goal of precision-based ILD management, we will complete three complementary Specific Aims. In Aim 1 we will determine if NAC is an effective treatment in IPF patients characterized by a precision genotype approach. In partnership with the PFF, we will identify PFF registry subjects with the TOLLIP T/T genotype to begin randomizing 200 IPF patients followed by enrolling new subjects at the same clinical sites to receive NAC or placebo in a double-blind fashion. This study, the “Prospective tReatment EffiCacy in IPF uSIng genOtype for Nac Selection (PRECISIONS)” trial, will document the benefits of an innovative “precision” genotype-specific study design of a well-tolerated and inexpensive therapy. In Aim 2 we will distinguish IPF from non-IPF ILDs using unbiased combinations of blood transcriptomics and proteomics. We propose to conduct RNA-seq and proteomics to characterize gene expression and protein biomarkers on the entire PFF registry cohort. We will define “signatures” for distinguishing IPF from non-IPF ILDs. Our unbiased approaches to `omics traits will be integrated to reveal `omics risk scores that define individual diseases, predict disease course, and response to therapy. In Aim 3 we will identify genetic variants playing a role in IPF risk. We will conduct whole genome sequencing of the entire PFF cohort to detect novel genetic associations for IPF and ILD risk. With sufficient power, we will assess both common and rare/infrequent variants in comparison to ethnically matched un-afflicted cases, and between ILD cohorts to meet our objective. This will establish the largest collection of its kind and establish quantitative trait loci for all `omics' data. The results of our proposed experiments will move ILD management, and IPF therapy, in particular, into the precision medicine era.