Preclinical Pulmonary Fibrosis, an opportune rare disease cohort

临床前肺纤维化，一个合适的罕见疾病队列

• 批准号: 10219354
• 负责人: David Albert Schwartz
• 金额: $ 94.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219354
• 关键词: Ancillary Study; Automobile Driving; Biological; Biological Markers; Biological Specimen database; Cicatrix; Clinical; Clinical assessments; Cohort Studies; Collaborations; Communities; Complex; Data; Development; Diagnosis; Diagnostic; Diagnostic radiologic examination; Disease; Disease Progression; Dominant Genetic Conditions; Dose; Drug Targeting; Early Diagnosis; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Family; Family history of; First Degree Relative; Genetic; Genetic Models; Genetic Risk; Genetic Transcription; Goals; Hamman-Rich syndrome; Heterogeneity; Individual; Interstitial Pneumonia; Intervention; Lead; Lung; Lung diseases; MUC5B gene; Medical Genetics; Molecular; Monitor; National Heart, Lung, and Blood Institute; Natural History; Nested Case-Control Study; Observational Study; Onset of illness; Outcome; Patient Selection; Phenotype; Physiological; Physiology; Play; Pneumonia; Population; Prediction of Response to Therapy; Predisposing Factor; Primary Prevention; Program Development; Protocols documentation; Public Health; Pulmonary Fibrosis; Questionnaires; Rare Diseases; Research; Risk; Risk Factors; Role; Sampling; Scanning; Secondary Prevention; Signs and Symptoms; Specimen; Standardization; Symptoms; Testing; Variant; Visit; Vital Status; base; biobank; case finding; clinical phenotype; clinically significant; cohort; data warehouse; drug development; follow-up; gain of function; genetic variant; genomic locus; high risk; high risk population; improved; interstitial; molecular phenotype; patient advocacy group; pre-clinical; preclinical development; prognostic; programs; promoter; prospective; study population; transcriptomics

ABSTRACT FDR from FIP Family Our proposed rare disease cohort focuses on a critical unmet public health need in (N=1000) interstitial pneumonia, to understand the etiology, natural history, and phenotypic N=650 Subcohort N=350 heterogeneity of preclinical pulmonary fibrosis (PrePF), before the lung is scarred irreversibly. Our overall hypothesis is that common genetic variants and 100 PrePF 50 PrePF environmental risk factors predispose to the development, natural history, 300 unaffected and phenotypic heterogeneity of PrePF, and that defining these risk factors will allow us to uncover the common and unique subtypes of PrePF that differ Case-Cohort at baseline in disease onset and progression. By leveraging our NHLBI-supported (150 Cases; 300 Unaffecteds) discoveries in PrePF, familial interstitial pneumonia (FIP), and idiopathic interstitial Figure 1. Relationship between pneumonia (IIP), and our NHLBI-supported cohort of FIP families, our proposal Subcohort and the original FIP seeks to explain how common genetic variants and the environment interact to cohort. Given the risk of PrePF FIP FDRs (15%), we anticipate result in the earliest stages of this highly morbid, phenotypically heterogeneous that 50 individuals in the disease. We will focus on first-degree relatives (FDRs) previously phenotyped as Subcohort will have PrePF at unaffected (N=2404) from our 1160 FIP families with two or more cases of baseline. Cases will be supplemented from the confirmed IIP. Within these 1160 FIP families, we will establish our rare disease remaining 650 subjects in the cohort of 1000 subjects by selecting up to two asymptomatic, previously phenotyped overall cohort so that our case- unaffected FDRs per family. To combine the advantages of our cohort with the cohort population at baseline should include 150 cases of efficiency of a nested case-control study, we will establish a case-cohort study and PrePF and 300 unaffecteds. compare 150 cases of PrePF to 300 unaffected controls (Figure 1). This approach will allow us to determine the individual and combined contributions of common genetic variants and environmental features that result in the development of PrePF. By focusing on the natural history of IIP, our results can be used to identify high-risk populations, early forms of the disease, factors associated with disease progression, and biological targets for drug development. Moreover, a natural history study can also identify critical biomarkers that can be diagnostic of early or established forms of the disease, prognostic of the course of a disease, predictive of treatment response, or useful in guiding patient selection and dose selection in drug development programs. Our proposal would establish a prospectively followed high-risk IIP cohort, will identify the genetic and environmental risk factors for PrePF, and will maximize the utility of this high-risk cohort for ancillary studies focused on primary and secondary prevention of IIP. 15% PrePF

从FIP家族中提取FDR 我们提出的罕见病队列重点关注（N=1000）中未满足的关键公共卫生需求 间质性肺炎，了解病因、自然史和表型N=650亚队列 N=350 临床前肺纤维化（PrePF）的异质性，在肺形成瘢痕之前 不可逆转我们的总体假设是，常见的遗传变异和100 PrePF 50 PrePF 环境风险因素易诱发发展，自然史，300不受影响 和PrePF的表型异质性，以及定义这些风险因素的 将使我们能够揭示PrePF的常见和独特亚型，这些亚型在基线时与病例队列不同 疾病的发生和发展。通过利用我们的NHLBI支持（150例; 300例未受影响） 在PrePF、家族性间质性肺炎（FIP）和特发性间质性肺炎中的发现图1。关系 肺炎（IIP），以及我们的NHLBI支持的FIP家族队列，我们的提案子队列和原始FIP 试图解释常见的遗传变异和环境如何与队列相互作用。考虑到PrePF的风险 FIP FDR（15%），我们预计 导致这种高度病态的，表型异质性的最早阶段， 疾病我们将重点关注先前进行表型分型的一级亲属（FDR），因为子队列将在 未受影响的（N=2404）从我们的1160 FIP家庭与两个或两个以上的情况下的基线。案件将 补充自 确认IIP。在这1160个FIP家族中，我们将在2015年确定我们的罕见疾病剩余650例受试者。 1000名受试者的队列，选择多达两个无症状的，以前的表型整体队列，使我们的情况- 每个家庭不受影响的FDR。联合收割机结合我们队列的优势和基线时的队列人群 应包括150例 为了验证巢式病例对照研究的有效性，我们将建立一个病例队列研究，并对PrePF和300名未受影响的患者进行研究。 将150例PrePF病例与300例未受影响的对照进行比较（图1）。这种方法 将使我们能够确定共同遗传变异的个体和组合贡献， 导致PrePF发展的环境特征。通过关注IIP的自然历史，我们的 结果可用于识别高危人群、疾病的早期形式、与疾病相关的因素， 进展和药物开发的生物靶点。此外，自然历史研究也可以确定 可以诊断疾病的早期或确定形式的关键生物标志物， 或用于指导药物治疗中的患者选择和剂量选择 发展方案。我们的建议将建立一个前瞻性随访的高风险IIP队列， PrePF的遗传和环境风险因素，并将最大限度地利用这一高风险队列， 辅助研究侧重于IIP的一级和二级预防。 15% PrePF