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

基本信息

批准号：
10683293
负责人：
David Albert Schwartz
金额：
$ 121.92万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683293
关键词：
Ancillary Study Automobile Driving Biological Biological Markers Cicatrix Classification Clinical Clinical assessments Cohort Studies Collaborations Communities Complex Data Databases Development Diagnosis Diagnostic 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 Genes Genetic Genetic Models Genetic Risk Genetic Transcription Goals Heterogeneity Idiopathic Interstitial Pneumonia Individual Interstitial Pneumonia Intervention Lung MUC5B gene 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 Random Allocation Rare Diseases Research Risk Risk Factors Role Sampling Scanning Secondary Prevention Signs and Symptoms Specimen Standardization Subjects Selections Symptoms Testing Variant Visit Vital Status biobank case finding clinical phenotype clinically significant cohort data warehouse drug development fibrotic lung fibrotic lung disease follow-up gain of function genetic risk factor genetic variant high risk high risk population improved interstitial molecular phenotype patient advocacy group pre-clinical preclinical development prognostic programs promoter prospective radiological imaging study population transcriptomics

项目摘要

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.

FIP 系列摘要 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 肺部结疤之前临床前肺纤维化 (PrePF) 的异质性不可逆转地。我们的总体假设是，常见的遗传变异和 100 PrePF 50 PrePF 环境风险因素导致发展，自然历史，300不受影响和 PrePF 的表型异质性，以及定义这些危险因素将使我们能够发现与基线病例队列不同的 PrePF 的常见和独特亚型在疾病的发生和进展中。通过利用我们的 NHLBI 支持（150 例；300 例未受影响） PrePF、家族性间质性肺炎 (FIP) 和特发性间质性肺炎的发现图 1. 之间的关系肺炎 (IIP)，以及我们 NHLBI 支持的 FIP 家庭队列、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群体相互作用。考虑到 PrePF 的风险我们预计 FIP FDR (15%) 导致这种高度病态、表型异质性的最早阶段，50个个体疾病。我们将重点关注先前表型为 PrePF 的一级亲属 (FDR) 我们 1160 个具有两个或更多基线病例的 FIP 家庭中未受影响 (N=2404)。案件将是补充自确认了国际投资头寸。在这 1160 个 FIP 家庭中，我们将确定我们的罕见病剩余 650 名受试者 1000 名受试者的队列，通过选择最多两个无症状、先前表型分析的整个队列，以便我们的病例- 每个家庭不受影响的 FDR。将我们队列的优势与基线队列人群的优势结合起来应包括 150 个案例为了提高巢式病例对照研究的效率，我们将建立病例队列研究和 PrePF 以及 300 名未受影响的患者。将 150 个 PrePF 病例与 300 个未受影响的对照进行比较（图 1）。这种做法将使我们能够确定常见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学目标。此外，自然历史研究还可以识别可以诊断疾病的早期或既定形式、病程预后的关键生物标志物疾病的预测、治疗反应的预测或有助于指导患者选择和药物剂量选择发展计划。我们的建议将建立一个前瞻性跟踪的高风险 IIP 队列，将确定 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人群辅助研究侧重于 IIP 的一级和二级预防。