Center for Integrated Approaches to Undiagnosed Diseases

未确诊疾病综合治疗中心

基本信息

批准号：
9251865
负责人：
Joseph Loscalzo
金额：
$ 228.29万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251865
关键词：
Address Adult Binding Bioinformatics Biological Assay Boston Child Clinical Clinical Data Clinical assessments Collaborations Communities Complement Copy Number Polymorphism DNA DNA Sequence DNA Sequence Analysis Data Data Analyses Data Collection Development Diagnosis Diagnostic Disease Disease Pathway Environment Environmental Exposure Environmental Risk Factor Etiology Evaluation Event Family member Gene Expression General Hospitals Genes Genetic Genetic Predisposition to Disease Genetic Variation Genomic approach Genomics Genotype Hospitals Image Individual Interdisciplinary Study Laboratories Lead Manuals Massachusetts Medical center Methods Molecular Network-based Occupational Pathway interactions Patient Recruitments Patients Pediatric Hospitals Phenotype Physiological Procedures Proteomics Protocols documentation Quality Control Recruitment Activity Research Infrastructure Sampling Site Standardization Syndrome Systems Biology Tissues United States National Institutes of Health Variant Woman Work analytical method base clinical phenotype clinical research site data resource disease classification disease diagnosis disease phenotype exome genetic variant genome sequencing improved insight interest meetings member metabolomics multiple omics novel operation programs public health relevance quality assurance response tool transcriptomics translational scientist whole genome

项目摘要

DESCRIPTION (provided by applicant): Undiagnosed diseases are likely to be determined by genetic, environmental, and developmental factors. While some undiagnosed diseases will represent novel rare genetic syndromes with monogenic or oligogenic etiologies and others will reflect rare manifestations of known diseases, many are likely to result from a more analytically challenging combination of multiple genetic, environmental, and developmental factors. Whole exome and whole genome sequencing are powerful tools with which to ascertain the genetic contributions to undiagnosed diseases; however, these methods alone are unlikely to elucidate the basis for many, if not most, undiagnosed diseases. The central unifying hypothesis of this proposal is, therefore, that an integrated, network-based, systems biology approach that incorporates not only genetic variation data, but also gene expression, metabolomic, proteomic, and exposomic data, along with careful deep phenotyping, will prove to be the most effective way to identify the pathways and mechanisms responsible for many undiagnosed diseases. To address the underlying hypothesis, we propose to establish an integrated interdisciplinary research plan for the Harvard Undiagnosed Disease Program Clinical Site (Harvard UDP-CS) that involves three specific aims: 1) ascertainment and clinical characterization - we will perform case ascertainment and phenotypic characterization for selected rare and undiagnosed disease states in adults and children; 2) genetic assessments - we will use patient and family member-derived DNA sequence, transcriptomic data (when available), and clinical phenotype information to identify potentially causal DNA sequence variants, gene expression variation, and potentially causative pathway derangements; and 3) network approach to disease diagnosis - we will integrate other -omic data, including metabolomic, proteomic, and exposomic data, along with the candidate genetic variants into the comprehensive interactome, and thereby identify diseases or disease pathways in network proximity to the involved genes that may help identify potential pathobiological modules relevant to the etiology of the undiagnosed disease. We will work toward meeting these specific aims and addressing the overall hypothesis in close collaboration with the coordinating center and other clinical sites in the UDN in order to develop and implement assessment protocols of phenotype, environment, and genotype that will ultimately define the etiology and treatment of undiagnosed diseases.

描述（由申请人提供）：未诊断的疾病可能取决于遗传，环境和发育因素。尽管一些未诊断的疾病将代表具有单基因或寡原性病因的新型稀有遗传综合症，而另一些疾病将反映已知疾病的罕见表现，但许多疾病可能是由于多种遗传，环境和发育因素的更具分析性挑战性的结合而引起的。整个外显子组和整个基因组测序是有力的工具，可以确定对未诊断疾病的遗传贡献；但是，仅这些方法就不太可能阐明许多（如果不是大多数）未诊断的疾病的基础。因此，该提案的核心统一假设是，一种集成的，基于网络的系统生物学方法不仅结合了遗传变异数据，而且还结合了基因表达，代谢组，蛋白质组学和拓博型数据，以及仔细的深层表型，将证明是确定负责无数次无限症的途径和机制的最有效的方法。为了解决基本假设，我们建议建立哈佛无诊断疾病计划临床部位（哈佛UDP -CS）的综合跨学科研究计划，该计划涉及三个特定目标：1）确定和临床表征 - 我们将执行。成人和儿童中选定的罕见和未诊断疾病状态的病例确定和表型表征； 2）遗传评估 - 我们将使用患者和家庭成员衍生的DNA序列，转录组数据（如果有）和临床表型信息来识别潜在的因果DNA序列变异，基因表达变异以及潜在的病毒途径危险；和3）疾病诊断的网络方法 - 我们将将其他 - 瘤数据集成，包括代谢组，蛋白质组学和外胚层数据，以及候选遗传变异型的候选遗传变异，从而确定与潜在的病理学模块化相关的潜在疾病，从而确定与涉及的基因相关的疾病或疾病途径。我们将努力实现这些特定目标，并与UDN中的协调中心和其他临床部位密切合作解决总体假设，以制定和实施表型，环境和基因型的评估方案，最终将定义未诊断疾病的病因和治疗。