Peripheral Blood Biomarkers for Idiopathic Interstitial Pneumonia

描述（由申请人提供）：本提案中涉及的广泛挑战领域是（03）生物标志物发现和验证，具体挑战主题是03-HL-101。本研究旨在提高特发性间质性肺炎（IIP）的早期诊断率，提高鉴别诊断特发性间质性肺炎亚型的能力。特发性间质性肺炎的当前诊断方法需要由具有该领域专业知识的医生在三级学术转诊中心进行最佳的综合诊断性临床、放射学和病理学测试。手术肺活检是必需的，并与额外的费用，发病率和死亡率。尽管做出了这些努力，但一些患者的诊断仍然不确定。我们寻求在疾病早期对特发性肺炎的各种亚型进行准确诊断，而不需要手术肺活检，并通过开发外周血标志物使这种方法在社区中更广泛地使用。我们以前对家族性间质性肺炎（FIP，定义为每个家族>例IIP）的研究表明，FIP在表型和遗传上是异质的，这表明多个基因引起IIP，并且这些个体遗传变异可能与区分这组复杂肺部疾病的特定分子特征相关。我们对160个有两个或两个以上IIP（家族性间质性肺炎，FIP）病例的家庭进行了表型分析，几年前报告了最初111个家庭的结果。在我们的家族性间质性肺炎患者（FIP）队列中，通过筛选未受影响的家庭成员，我们已经确定了具有早期疾病以及有症状的晚期疾病的症状前受试者，从而收集了跨越整个疾病谱的患者。我们使用该队列，使用外周血基因表达谱开发外周血中FIP的分子特征。我们确定了一个外周血转录组，区分14个临床前和症状的患者从11个健康对照。因此，我们假设特发性间质性肺炎（IIP）的外周血生物标志物或生物特征（基因或蛋白质表达模式）将简化和提高IIP诊断的准确性，并在疾病的早期、更可治疗的阶段诊断个体。我们计划通过使用我们的具有症状前疾病的FIP队列来鉴定可以鉴定早期疾病的生物标志物，并且该FIP队列具有多种IIP亚型。特发性间质性肺炎（IIP）是一种广谱的慢性纤维化肺部疾病，可导致无法治疗的呼吸衰竭。虽然在理解这些疾病的临床、放射学和病理学表现方面已经取得了实质性进展，但临床医生仍然难以从其他类型的间质性肺病中诊断IIP，特别是识别IIP的不同亚型。拟议项目的总体目标是开发和验证外周血中的分子特征，以完善IIP的诊断标准。复杂疾病组;一旦确定了IIP的这些分子特征，就可以在未来的研究中进行测试，以增强早期检测、预测结果和塑造个性化的治疗策略。我们将在未来2年内为这项工作创造2个新的工作岗位，并有可能在未来创造更多的工作岗位，以开发标准化的临床诊断实验室检测。

DESCRIPTION (provided by applicant): The Broad Challenge Area addressed in this proposal is (03) Biomarker Discovery and Validation, and the Specific Challenge Topic is 03-HL-101. The purpose of this proposal is to improve the accurate and early diagnosis of idiopathic interstitial lung pneumonia (IIP), and to improve the ability to differentiate the subtypes of idiopathic interstitial pneumonias (IIPs). The current diagnostic approach to idiopathic interstitial pneumonias requires comprehensive diagnostic clinical, radiologic, and pathologic testing optimally performed in tertiary academic referral centers by physicians with expertise in this field. Surgical lung biopsy is required, and is associated with additional cost, morbidity, and mortality. Despite these efforts, the diagnosis in some patients remains uncertain. We seek to make an accurate diagnosis of the various subtypes of idiopathic pneumonias early in the course of the disease without the need for surgical lung biopsy, and to make this approach more widely available in the community by developing peripheral blood markers. Our previous work with familial interstitial pneumonia (FIP, defined as > cases of IIP per family) indicates that FIP is phenotypically and genetically heterogeneous, suggesting that multiple genes cause IIP and that these individual genetic variants are likely to be associated with specific molecular signatures that distinguish this group of complex lung diseases. We have phenotyped 160 families with two or more cases of IIP (familial interstitial pneumonia, FIP) and several years ago reported the findings from the initial 111 families. Within our cohort of familial interstitial pneumonia patients (FIP), by screening unaffected family members, we have identified pre-symptomatic subjects with early disease as well as symptomatic, later stage disease thus collecting patients that span the entire spectrum of disease. We used this cohort to develop a molecular signature of FIP in peripheral blood using peripheral blood gene expression profiles. We identified a peripheral blood transcriptome that distinguishes 14 preclinical and symptomatic patients from 11 healthy controls. Thus, we hypothesize that a peripheral blood biomarker or biological signature (gene or protein expression pattern) of idiopathic interstitial pneumonias (IIPs) will simplify and improve the accuracy of diagnosis of IIP and diagnose individuals at an earlier, more treatable, stage of their disease. We plan to identify a biomarker that can identify early stage disease by using our FIP cohort with pre- symptomatic disease, and that has multiple subtypes of IIP. Idiopathic interstitial pneumonia (IIP) represents a broad spectrum of chronic fibrosing lung conditions that can lead to untreatable respiratory failure. While substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of these disorders, it remains difficult for the clinician to diagnose IIP from other types of interstitial lung disease, particularly to identify the different subtypes of IIP The overall goal of the proposed project is to develop and validate molecular signatures in the peripheral blood that serve to refine the diagnostic criteria for this group of complex diseases; once established these molecular signatures of IIP could be tested in future studies to enhance early detection, to predict outcome, and to mould personalized therapeutic strategies. We will create 2 new job positions for this work over the next 2 years, and the potential to create more in the future to develop standardized clinical diagnostic laboratory assays.