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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：
10594397
负责人：
Beth A Kozel
金额：
$ 63.92万
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/10594397
关键词：
Address Affect Aneurysm Aorta Aortic Valve Stenosis Area Awareness Basic Science Biological Blood Vessels C-terminal Case Study Cell Line Characteristics Chronic Obstructive Pulmonary Disease Clinical Clinical Data Clinical Research Code Collaborations Communities Community Health Connective Tissue Connective Tissue Diseases Cutis Laxa Data Defect Diagnosis Diameter Disease Disease model Doctor of Philosophy Elastic Fiber Elastic Tissue Elasticity Elastin Electronic Health Record 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 System Tissues Translational Research Translations United States National Institutes of Health Variant Work arterial tortuosity autosome burden of illness clinical application clinical center clinical phenotype clinically relevant cohort comparison control 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 participant enrollment phenotypic data population based premature profiles in patients protein function protein structure rare variant success text searching treatment strategy variant of interest

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.

总结