CTRIP: Molecular phenotypes of rapidly progressive idiopathic pulmonary fibrosis

描述（由申请人提供）：特发性肺纤维化进展的分子标志物。本申请涉及以下NHLBI参与研究和研究基础设施“重大机遇”RC2主题：携程：NHLBI转化研究实施计划。特发性肺纤维化（IPF）是一种进行性、致死性肺纤维化疾病，在美国的患病率估计为30-80/10万，但其发病率明显上升(1)。在过去的十年中，特发性间质性肺炎（IPF是其中之一）的组织病理学分类的改进有助于区分对治疗有反应的疾病与那些预后不良且对已知治疗相对无反应的疾病。最常见的特发性间质性肺炎是IPF，其组织病理类型为间质性肺炎。IPF与所有iip的最差预后相关，自诊断时起的中位生存期为30-40个月。尽管已经进行了许多治疗性临床试验，以减缓肺纤维化的无情进展，但没有一个明确确定有益的治疗方案。当出现典型的临床症状、体征和影像学表现时，可以自信地诊断IPF。做出准确的诊断是至关重要的，因为IPF诊断驱动整体预后，对选择有限的可用治疗方法至关重要，包括肺移植。IPF患者护理的另一个主要挑战是确定预后。IPF的自然病史通常是肺功能的进行性下降，最终导致呼吸衰竭死亡。然而，IPF的纵向生理性下降在个体患者中是相当不均匀的，难以预测。最近报道的两项吡非尼酮试验的不一致结果突出了这种疾病进展变异性的实际含义。在两项研究中，吡非尼酮治疗组在随访期间预测的FVC百分比下降相似（6.49%），而安慰剂组在一项研究中下降了9.55%，在另一项研究中下降了7.23%。这一差异导致了与主要分析结果截然不同的结果（第一次p=0.001，第二次p=0.501）。由于许多目前的治疗研究强调大约一年的结果，识别有快速疾病进展风险的患者的能力将为临床试验的设计纳入和排除标准以及临床实践中对药物治疗的临床反应的解释提供关键的临床优势。已经采取了不同的生理方法来识别疾病进展，主要基于识别有死亡风险的患者的能力，结果各不相同。我们的研究小组改进了生理方法，通过将FVC、DLCO或6分钟步行表现的纵向变化分层作为基线6分钟步行去饱和的函数来定义生理疾病进展（13）。FVC降低10%或DLCO降低至少15%被证明可以预测随后的死亡率。不幸的是，生理恶化与临床事件之间的不完全关系支持疾病进展最好使用复合方法来定义，包括FVC和/或DLCO减少、急性加重或死亡率。目前，该方法被用作一系列NIH （ACE研究）或行业赞助的治疗试验（ARTEMIS Study & BUILD 3）的主要终点。确定IPF患者保持稳定与进展之间的生物学相关差异是一个关键的研究领域。几个研究小组使用不完整或未经验证的方法来定义中间疾病进展，他们认为肺组织或血液或支气管肺泡灌洗液中标记物的基因表达存在差异。我们的初步数据表明，TLR9（一种低甲基化的CpG DNA受体）在快速进展性IPF患者的外科肺活检（SLB）中显著表达。此外，与来自同一患者的slb来源的成纤维细胞相比，经支气管活检（TBB）衍生的IPF成纤维细胞表现出相似的迁移和增殖特性。外周血单核细胞mRNA全基因组表达阵列的额外初步数据表明了一个快速进展的信号，因此，很明显，了解IPF进展生物学的下一个主要进展将来自以标准方式研究高度特征性患者的生物样本。我们假设生物标志物将可靠地识别在前45周随访期间进展迅速的IPF患者。我们将解决两个具体目标：1)组建一个临床中心网络，从最近诊断为IPF的患者中获取生物样本，并对这些患者进行至少45周的随访；2)将从同一患者的多个隔室（SLB、TBB、血液）获得的疾病活动性生物标志物与疾病进展的纵向测量相关联和整合。这种全面的方法将使人们对渐进式指间因子的生物学基础有前所未有的了解，并允许在基线访问时对其进行定义。

DESCRIPTION (provided by applicant): Molecular Markers of Idiopathic Pulmonary Fibrosis Progression. 2. Specific Aims this application addresses the following NHLBI participation in Research and Research Infrastructure "Grand Opportunities" RC2 TOPIC: CTRIP: NHLBI Translational Research Implementation Program. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal, fibrotic disorder of the lung with an estimated prevalence of 30-80/100,000 in the United States but whose incidence is clearly rising (1). Over the last decade, improved histopathologic classification of the idiopathic interstitial pneumonias (of which IPF is one) has helped to distinguish disorders which are responsive to therapy from those which are associated with a poor prognosis and are relatively unresponsive to known therapies. The most common idiopathic interstitial pneumonia (IIP) is IPF, whose histopathologic pattern is usual interstitial pneumonia. IPF is associated with the worst prognosis of all IIPs with a median survival of 30-40 months from the time of diagnosis. Although numerous therapeutic clinical trials have been undertaken to slow the relentless progression of fibrosis in the lung, none has clearly identified a beneficial therapeutic regimen. The diagnosis of IPF can be confidently made when typical clinical symptoms, signs and radiographic findings are present. Making an accurate diagnosis is critical as an IPF diagnosis drives overall prognosis and is crucial to selecting the limited available therapies, including lung transplantation. An additional major challenge in the care of IPF patients is determining prognosis. The natural history of IPF is usually one of progressive decline in lung function that ultimately results in death from respiratory failure. However, longitudinal physiologic decline in IPF is quite heterogeneous and difficult to predict in individual patients. The practical implication of this variability in disease progression is highlighted by the discordant results of two recently reported pirfenidone trials. In both studies, the pirfenidone treated group exhibited a similar decrease in FVC percent predicted over follow-up (6.49%) while the placebo group decreased by 9.55% in one study and 7.23% in the other. This difference resulted in vastly different results from the primary analyses (p=0.001 in one and p=0.501 in the second). As many current treatment studies emphasize approximately one year outcomes, the ability to identify patients at risk for rapid disease progression would provide a key clinical advantage in the design inclusion and exclusion criteria for clinical trials and the interpretation of clinical responses to drug therapies in clinical practice. Disparate physiological approaches have been taken to identify disease progression, largely based on the ability to identify patients at risk of mortality, with varying results. Our group has refined the physiological approach to defining physiological disease progression by stratifying longitudinal change in FVC, DLCO or six minute walk performance as a function of baseline six-minute walk desaturation (13). An FVC decrease > 10% or a DLCO decrease of at least 15% was shown to strongly predict subsequent mortality. Unfortunately, the incomplete relationship between physiological worsening and clinical events supports that disease progression is best defined using a composite approach including decreasing FVC and/or DLCO, acute exacerbations or mortality. This approach is now being utilized as the primary endpoint in a series of NIH (ACE Study) or industry sponsored therapeutic trials (ARTEMIS Study & BUILD 3). Identifying biologically relevant differences between IPF patients that remain stable versus those who progress is a crucial area of investigation. Several investigative groups, using incomplete or unvalidated methods to define intermediate disease progression, have suggested differences in gene expression of lung tissue or markers in blood or bronchoalveolar lavage. Our preliminary data indicate that TLR9, a hypomethylated CpG DNA receptor, is prominently expressed in surgical lung biopsies (SLB) from rapidly progressive IPF patients. Furthermore, IPF transbronchial biopsies (TBB)-derived fibroblasts exhibit similar migratory and proliferative properties compared with SLB-derived fibroblasts from the same patients. Additional preliminary data in peripheral blood monocyte mRNA whole genome expression arrays indicate a signature suggestive of rapid progression, Thus, it is clear that the next major advances in understanding the biology of IPF progression will come from studying biologic samples in highly characterized patients followed in a standard fashion. We hypothesize that biomarkers will reliably identify IPF patients who progress rapidly during the first 45 weeks of follow-up. We will address two Specific Aims: 1) Assemble a network of clinical centers to procure biologic samples from patients with recently diagnosed IPF and follow these patients for at least 45 weeks; 2) Correlate and integrate biologically plausible biomarkers of disease activity obtained from multiple compartments (SLB, TBB, blood) from the same patient with longitudinal measures of disease progression. This comprehensive approach will allow an unprecedented understanding of the biological underpinnings of progressive IPF and allow its definition at a baseline visit. PUBLIC HEALTH RELEVANCE: Early diagnosis of Idiopathic Pulmonary Fibrosis (IPF) is key to providing the appropriate treatment for this incurable disease. This project will quickly enroll 135 clinical subjects from across the United States. The multiple specimens collected from this population will be used over a two year period by the nation's leading IPF basic science and clinical research teams to determine the early indicators of the ability to maintain stable health.