CTRIP: Molecular phenotypes of rapidly progressive idiopathic pulmonary fibrosis

描述(申请人提供)：特发性肺纤维化进展的分子标志物。2.具体目标本申请涉及以下NHLBI参与研究和研究基础设施的重大机遇RC2主题：携程：NHLBI翻译研究实施计划。特发性肺纤维化(IPF)是一种进行性、致命性、纤维性肺疾病，在美国的患病率估计为30-80/100,000，但其发病率明显上升。在过去的十年中，改进的特发性间质性肺炎(IPF是其中之一)的组织病理学分类有助于区分对治疗有反应的疾病和那些与预后不良相关的疾病，以及对已知治疗相对无效的疾病。特发性间质性肺炎(IIP)是最常见的间质性肺炎，其组织病理类型为普通型间质性肺炎。IPF是所有IIPS中预后最差的，从确诊之日起中位生存期为30-40个月。虽然已经进行了许多治疗临床试验来减缓肺纤维化的持续进展，但还没有明确确定一种有益的治疗方案。当出现典型的临床症状、体征和放射学表现时，可以自信地做出IPF的诊断。做出准确的诊断是至关重要的，因为IPF的诊断决定了整体预后，并且对于选择有限的可用治疗方法至关重要，包括肺移植。IPF患者护理中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的纵向生理性下降是非常不均匀的，在个体患者中很难预测。最近报道的两个吡非尼酮试验的不一致结果突显了这种变异性在疾病进展中的实际意义。在这两项研究中，吡非尼酮治疗组的FVC预测百分比在随访期间显示出类似的下降(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非常不同的结果(第一次分析中p=0.001，第二次分析中p=0.501)。由于目前的许多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在设计临床试验的纳入和排除标准以及在临床实践中解释药物治疗的临床反应方面提供关键的临床优势。已经采取了不同的生理学方法来确定疾病的进展，主要基于识别有死亡风险的患者的能力，结果各不相同。我们小组改进了生理学方法，通过将FVC、DLCO或六分钟步行表现的纵向变化分层为基线六分钟步行去饱和度的函数来定义生理性疾病进展(13)。FVC下降10%或DLCO下降至少15%被显示为强烈预测后续死亡率。不幸的是，生理性恶化和临床事件之间的不完全关系支持了疾病进展的最佳综合方法，包括降低FVC和/或DLCO、急性恶化或死亡率。这种方法现在被用作一系列NIH(ACE研究)或行业赞助的治疗试验(Artemis Study&Build 3)的主要终点。确定保持稳定的IPF患者与进展的IPF患者之间的生物学相关差异是一个关键的调查领域。几个研究小组使用不完全或未经验证的方法来定义中间疾病进展，提出了肺组织的基因表达或血液或支气管肺泡灌洗液中的标志物的差异。我们的初步数据表明，TLR9，一种低甲基化的CpG DNA受体，在快速进展的IPF患者的外科肺活检(SLB)中显著表达。此外，IPF经支气管镜活检(TBB)来源的成纤维细胞与来自相同患者的SLB来源的成纤维细胞相比，具有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显示了快速进展的特征，因此，很明显，理解IPF进展的生物学方面的下一个重大进展将来自于以标准方式跟踪研究高度特征化的患者的生物样本。我们假设生物标记物将可靠地识别在随访的前45周内进展迅速的IPF患者。我们将解决两个具体目标：1)建立一个临床中心网络，从最近诊断为IPF的患者那里获取生物样本，并对这些患者进行至少45周的跟踪；2)将从同一患者的多个隔室(SLB、TBB、血液)获得的生物学上看似合理的疾病活动生物标记物与疾病进展的纵向测量进行关联和整合。这一综合办法将使人们能够前所未有地了解进步的森林小组的生物学基础，并允许在基线访问中对其进行定义。 公共卫生相关性：特发性肺纤维化(IPF)的早期诊断是为这种不治之症提供适当治疗的关键。该项目将很快从全美招募135名临床受试者。从这一人群中收集的多个样本将在两年内由全国领先的IPF基础科学和临床研究团队使用，以确定维持稳定健康的能力的早期指标。

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.