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家族的抽象FDR 我们提出的罕见疾病队列的重点是（n = 1000）的关键未满足的公共卫生需求间质性肺炎，以了解病因，自然史和表型n = 650 subpotort n = 350 在肺部被伤痕累累之前不可逆转。我们的总体假设是常见的遗传变异和100个Prepf 50 Prepf 环境风险因素易感发展，自然历史，300不受影响 PrepF的表型异质性，并定义这些风险因素我们将允许我们发现基线时案例 - 托尔特不同的普通和独特的亚型在疾病发作和进展中。通过利用我们的NHLBI支持的（150例； 300例未受影响） Prepf，家族性肺炎（FIP）和特发性间质性图1的发现。肺炎（IIP）和我们的NHLBI支持的FIP家族，我们的提案子院和原始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的最早阶段，有50个人疾病。我们将重点关注以前表现为子病毒的一级亲戚（FDR）来自我们1160 FIP家族的未受影响（n = 2404），具有两个或多个基线病例。案件将是补充确认IIP。在这1160个FIP家族中，我们将建立我们的罕见疾病，剩下的650名受试者通过选择多达两个无症状的，以前表现为总体总体的1000名受试者的队列，以使我们的病例 - 每个家庭未受影响的FDR。将我们队列的优势与基线的队列人口相结合应包括15例一项嵌套的病例对照研究的效率，我们将建立一项病例研究研究和预备以及300个未受影响的人。将150例PrepF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常见遗传变异的个体和综合贡献导致PrepF发展的环境特征。通过专注于IIP的自然历史，我们结果可用于识别高风险人群，早期形式的疾病，与疾病相关的因素进展和药物开发的生物学靶标。而且，自然史研究也可以识别可以诊断为早期或已建立的疾病形式的关键生物标志物，预后疾病，预测治疗反应或有用的药物选择和剂量选择开发计划。我们的建议将建立前瞻性追踪的高风险IIP队列，将确定 PrePF的遗传和环境风险因素，并将最大化此高风险队列的实用性辅助研究的重点是对IIP的初级和次要预防。