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:
- 金额:$ 63.92万
- 依托单位:
- 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:
- 关键词:AddressAffectAneurysmAortaAortic Valve StenosisAreaAwarenessBasic ScienceBiologicalBlood VesselsC-terminalCase StudyCell LineCharacteristicsChronic Obstructive Pulmonary DiseaseClinicalClinical DataClinical ResearchCodeCollaborationsCommunitiesCommunity HealthConnective TissueConnective Tissue DiseasesCutis LaxaDataDefectDiagnosisDiameterDiseaseDisease modelDoctor of PhilosophyElastic FiberElastic TissueElasticityElastinElectronic Health RecordEnsureExtramural ActivitiesFBLN5 geneFamilyFamily history ofFibroblastsFrequenciesFunctional disorderGeneral PopulationGenesGeneticGenetic VariationGenetic studyGenomic medicineGenomicsGenotypeGoalsHealthHealth systemHumanHypertensionIcebergIn VitroIndividualInstitute of Medicine (U.S.)InstitutionIntracranial AneurysmInvestigationLaboratoriesLeadLeadershipLearningLinkLiteratureLungLung diseasesMediatingMedicalMedical RecordsMethodsMiningMutationOnline Mendelian Inheritance In ManParticipantPathogenicityPatientsPenetrancePhenotypePhysiciansPopulationProtein-Lysine 6-OxidaseProteinsPublishingPulmonary EmphysemaRare DiseasesRecording of previous eventsRecordsResearchResearch PersonnelResearch Project GrantsSamplingSkinStretchingSystemTissuesTranslational ResearchTranslationsUnited States National Institutes of HealthVariantWorkarterial tortuosityautosomeburden of illnessclinical applicationclinical centerclinical phenotypeclinically relevantcohortcomparison controlelectronic structureexomeexome sequencingexperiencefibulin-4genetic pedigreegenetic testinggenetic variantgenomic datahuman diseaseimprovedin vitro Modelindividual patientinduced pluripotent stem cellinnovationinsightinterestmultidisciplinarynovelnovel strategiesparticipant enrollmentphenotypic datapopulation basedprematureprofiles in patientsprotein functionprotein structurerare variantsuccesstext searchingtreatment strategyvariant 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Beth A Kozel其他文献
Beth A Kozel的其他文献
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{{ truncateString('Beth A Kozel', 18)}}的其他基金
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
- 批准号:
10368060 - 财政年份:2020
- 资助金额:
$ 63.92万 - 项目类别:
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
- 批准号:
9916513 - 财政年份:2020
- 资助金额:
$ 63.92万 - 项目类别:
IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY IN MICE
小鼠弹性蛋白单倍体不足的遗传修饰符的鉴定
- 批准号:
8306106 - 财政年份:2011
- 资助金额:
$ 63.92万 - 项目类别:
IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY IN MICE
小鼠弹性蛋白单倍体不足的遗传修饰符的鉴定
- 批准号:
8164890 - 财政年份:2011
- 资助金额:
$ 63.92万 - 项目类别:
IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY
弹性蛋白单倍体不足的遗传修饰符的鉴定
- 批准号:
8695456 - 财政年份:2011
- 资助金额:
$ 63.92万 - 项目类别:
IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY
弹性蛋白单倍体不足的遗传修饰符的鉴定
- 批准号:
8502340 - 财政年份:2011
- 资助金额:
$ 63.92万 - 项目类别:
IDENTIFICATION OF GENETIC MODIFIERS OF ELASTIN HAPLOISNSUFFICIENCY
弹性蛋白单倍体不足的遗传修饰符的鉴定
- 批准号:
8874263 - 财政年份:2011
- 资助金额:
$ 63.92万 - 项目类别:
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