Collaborative Research to Explore Genetic Variation and Phenotypic Spectrum of Elastin and Related Genes

探索弹性蛋白及相关基因的遗传变异和表型谱的合作研究

基本信息

批准号：
9916513
负责人：
Beth A Kozel
金额：
$ 53.81万
依托单位：
GEISINGER CLINIC
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：
2020-03-20 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9916513
关键词：
Address Affect Aneurysm Aortic Valve Stenosis Area Awareness Basic Science Biological Blood Vessels C-terminal Caliber Case Study Cell Line Characteristics Chronic Obstructive Airway Disease Clinical Clinical Data Clinical Research Code Collaborations Communities Community Health Connective Tissue Connective Tissue Diseases Cutis Laxa Data Defect Diagnosis Disease Disease model Doctor of Philosophy Elastic Fiber Elastic Tissue Elastin Electronic Health Record Enrollment Ensure Extramural Activities FBLN5 gene Family Family history of Fibroblasts Frequencies Functional disorder General Population Genes Genetic Genetic Variation Genetic study Genomic medicine Genomics Genotype Goals Health Health system Human Hypertension Iceberg In Vitro Individual Institute of Medicine (U.S.)Institution Intracranial Aneurysm Investigation Laboratories Lead Leadership Learning Link Literature Lung Lung diseases Mediating Medical Medical Records Methods Mining Mutation Online Mendelian Inheritance In Man Participant Pathogenicity Patients Penetrance Phenotype Physicians Population Protein-Lysine 6-Oxidase Proteins Publishing Pulmonary Emphysema Rare Diseases Recording of previous events Records Research Research Personnel Research Project Grants Sampling Skin Stretching Tissues Translational Research Translations United States National Institutes of Health Variant Work arterial tortuosity base burden of illness clinical application clinical center clinical phenotype clinically relevant cohort electronic structure exome exome sequencing experience fibulin-4 genetic pedigree genetic testing genetic variant genomic data human disease improved in vitro Model individual patient induced pluripotent stem cell innovation insight interest multidisciplinary novel novel strategies phenotypic data population based premature profiles in patients protein structure function rare variant success text searching treatment strategy

项目摘要

Summary In the past, new diseases were delineated when clinicians brought together a cohort of individuals with similar phenotypic characteristics. They then performed genetic testing and looked for shared genetic changes among the affected cohort. While this method proved successful in some cases, discovery was limited to disorders with relatively few genes and highly distinctive presentation. Since the advent of exome sequencing, physicians have become increasingly aware of the wide spectrum of variability of clinical features associated with previously known genes, with the actual manifestations attributable to a genetic variation being far greater than what was previously anticipated--the proverbial, “iceberg effect.” Overcoming these challenges requires a new approach. Instead of starting with the defined phenotype, we propose starting at the gene and working our way forward to identify the full spectrum of phenotypes that can arise from these genetic variations. Such work requires high numbers of well-phenotyped and genotyped samples, as well as the expertise to appropriately evaluate patients of interest. This application brings together two institutions with the experience and capability to do just that. The Geisinger Health System maintains extensive medical records and genotype and sequence data on more than 141,000 participants enrolled in the MyCode Community Health Initiative and has the expertise to mine those records and genomic sequences for meaningful and medically relevant associations. The NIH has expertise in the deep phenotyping and discovery in rare disease. For proof of principle that this gene-first strategy works, we are beginning our analysis into elastic fiber mediated connective tissue disease, an area with which our NIH collaborators have significant expertise. Previous literature linked changes in elastic fiber genes to defects in aortic diameter and tortuosity, lung changes such as emphysema and skin changes including laxity with more recent work suggesting connections to more common phenotypes such as hypertension, intracranial aneurysm, and chronic obstructive pulmonary disease. Our goal is to define all phenotypes, rare and common, associated with elastic fiber disease and to investigate the mechanism by which variation in these genes produces phenotypes in order to develop novel treatment strategies. In order to achieve this goal, we have developed two specific aims combining the strengths of Geisinger and the National Institutes of Health investigators. Aim 1. A) Screen an unselected population for variants in elastin and other elastic fiber genes and B) correlate with phenotypic features mined from the electronic health record. Aim 2: Identify previously unidentified phenotypes in patients with known and novel damaging variants in elastic fiber genes through deep phenotyping and disease modeling in vitro functional analysis. Collaboration between the two institution's diverse and multidisciplinary teams will increase understanding about the impact of elastic fiber disease and provide insight leading to treatment of human disease.

概括过去，当临床医生聚集了一群具有相似人群表型特征。然后，他们进行了基因检测，并寻找共享的遗传变化受影响的队列。虽然这种方法在某些情况下被证明是成功的，但发现仅限于疾病具有相对较少的基因和高度独特的表现。自从Exome测序冒险以来，医师已经越来越意识到与临床特征相关的广泛变异性具有先前已知的基因，实际表现归因于遗传变异要大得多比以前预期的东西 - 众所周知的“冰山效应”。克服这些挑战需要一个新方法。我们没有从定义的表型开始，而是提出从基因开始并开始工作前进，以识别这些遗传变异可能引起的全部表型。这样的工作需要大量的精美和基因分型样品，以及适当的专业知识评估感兴趣的患者。该应用程序汇集了两个具有经验和能力的机构做到这一点。 Geisinger Health System保持广泛的医疗记录以及基因型和顺序关于参加MyCode社区健康计划的141,000多名参与者的数据，并具有为有意义和医学相关的关联开采这些记录和基因组序列的专业知识。 NIH在稀有疾病的深层表型和发现方面具有专业知识。为了证明这一点基因优先策略有效，我们开始分析弹性纤维介导的结缔组织疾病，我们的NIH合作者具有重要专业知识的领域。以前的文献将变化联系在一起弹性纤维基因可在主动脉直径和曲折性中缺陷，肺部变化，例如肺气肿和皮肤包括松懈在内的变化，最近的工作表明与更常见的表型联系，例如高血压，颅内动脉瘤和慢性阻塞性肺部疾病。我们的目标是定义所有表型，罕见且常见，与弹性纤维疾病有关，并通过这些基因的变异会产生表型，以制定新的治疗策略。为了实现这一目标，我们开发了两个具体目标，结合了盖辛格和民族的优势卫生研究院研究人员。目标1。a）筛选弹性蛋白和其他变体的未选择人群弹性纤维基因和b）与电子健康记录开采的表型特征相关。目标2：识别弹性纤维中已知和新型破坏性变异的患者中先前未识别的表型通过深层表型和疾病建模的体外功能分析的基因。之间的协作两个机构的潜水员和多学科团队将增加对弹性光纤影响的理解疾病并提供洞察力，导致治疗人类疾病。