Elucidating novel mechanisms for glucocorticoid-induced ocular hypertension
阐明糖皮质激素诱发高眼压的新机制
基本信息
- 批准号:10317056
- 负责人:
- 金额:$ 78.19万
- 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:2020-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:Alternative TherapiesAntiinflammatory EffectBlindnessCellsClinicalClinical ManagementCodeComplicationDNADataDevelopmentDexamethasoneDiseaseDisease OutcomeEarEndothelial CellsEnrollmentExhibitsExposure toEyeEye diseasesFamily history ofFormulationFunctional disorderGenesGeneticGenetic Predisposition to DiseaseGenetic TranscriptionGenetic VariationGenetic studyGenomeGenotypeGlaucomaGlucocorticoidsHealthcareHumanInjectionsInstitutesLeadMassachusettsMeasurementMedicineMethodsMorbidity - disease rateOcular HypertensionOpen-Angle GlaucomaOphthalmologyOptic NerveParticipantPatientsPersonsPharmacologyPhenotypePhysiologic Intraocular PressurePlayPredispositionPrimary Open Angle GlaucomaProbabilityRecording of previous eventsResponse ElementsRiskRisk FactorsRoleSample SizeSamplingSourceSteroidsStructure of sinus venosus of scleraSuggestionSusceptibility GeneTestingTrabecular meshwork structureTranscriptUntranslated RNAValidationVariantbiobankcell typecohortcost efficientexomeexome sequencingexposed human populationfollow-upgenetic risk factorgenetic variantgenome wide association studygenome-widegenomic datahigh riskin silicoinsightnovelpressurerare variantrecruitscreeningsteroid hormonesurveillance strategytargeted sequencingtraittranscriptometranscriptome sequencingvariant detection
项目摘要
Project Summary/Abstract
Background Information and Relevance: Glucocorticoids (GC) are widely used in ophthalmology and in
medicine in general. GC-induced ocular hypertension (OHTN) is a common complication that can be
potentially blinding. The rate of this complication for GC injected intravitreally varies between 28-34%
depending on the formulation injected. This complication's risk factors are not well understood but there is
long-standing evidence that genetic factors play a role. Few genetic studies have been undertaken to identify
the implicated variants and no consistent findings have been identified. Hypotheses: Genetic susceptibility to
GC-induced OHTN is due to both common and rare variation, and associated variants are more likely to be
found in genes with transcripts altered by exposure to GC as well as genes that have glucocorticoid response
elements (GREs) or have been associated with primary open angle glaucoma (POAG) or intraocular pressure
(IOP). Specific Objectives: 1.To characterize the GC transcriptome in human trabecular meshwork (TM) cells
and Schlemm's canal endothelial (SCE) cells. 2. To perform genome-wide genotyping and whole exome
sequencing (WES) on 1086 patients with intravitreal GC injection exposure. 3. To identify common and rare
genetic variants in both coding and non-coding regions that are associated with GC-induced IOP elevation.
Methods: We will expose human TM and SCE cells to dexamethasone as well as media controls and perform
RNA sequencing to identify genes that are transcriptionally regulated by GCs. We will perform genome-wide
genotyping and WES on 1086 patients who have received an intravitreal GC injection and have serial IOP
measurements. Genotyping and WES will be performed as a cost efficient approach for the analyses
proposed. We will examine the GC-induced OHTN both as a quantitative trait of change in IOP adjusted for
baseline IOP and a dichotomous trait (GC responders vs. non-responders). We will execute genome-wide
association and WES analyses as well as targeted analyses. We will target variants in genes that are
transcriptionally regulated by GCs as identified in Aim 1, in loci with GREs, and in genes previously associated
with IOP or POAG. We will examine rare variants in the same loci for association with disease outcome using
aggregate and burden tests. We will enroll a replication cohort of 530 participants and perform targeted
sequencing to follow up suggestive or significant findings from the discovery analyses. We will also perform in
silico replication of these findings in three external cohorts with existing genomic data. Implications: If genes
associated with GC-induced IOP rise are identified, they will not only provide insights into this complication's
pathophysiology, but also into POAG mechanisms more broadly. Our findings will have implications for clinical
management of patients on GC. If we are able to identify patients at risk of GC-induced OHTN, we may avoid
morbidity by using alternative therapies or increasing surveillance while patients receive GC.
项目总结/摘要
背景信息和相关性:糖皮质激素(GC)广泛应用于眼科,
一般的医学。GC诱导的高眼压(OHTN)是一种常见的并发症,
可能致盲。玻璃体内注射GC的并发症发生率在28-34%之间
这取决于注射的制剂。这种并发症的风险因素还不清楚,但有
长期以来的证据表明遗传因素发挥了作用。很少有遗传学研究能够确定
没有发现相关的变体,也没有发现一致的结果。假设:遗传易感性
GC诱导的OHTN是由于常见和罕见的变异,相关的变异更可能是
发现于因暴露于GC而改变转录的基因以及具有糖皮质激素反应的基因中
或与原发性开角型青光眼(POAG)或眼内压相关
(IOP)。具体目的:1.鉴定人小梁网(TM)细胞中GC转录组
和Schlemm管内皮(SCE)细胞。2.进行全基因组基因分型和全外显子组
对1086名玻璃体内GC注射暴露的患者进行WES测序。3.来鉴别普通和稀有
与GC诱导的IOP升高相关的编码区和非编码区的遗传变异。
方法:我们将人TM和SCE细胞暴露于地塞米松以及培养基对照并进行
RNA测序以鉴定受GC转录调控的基因。我们将在全基因组范围内
对1086例接受玻璃体内GC注射并有连续IOP的患者进行基因分型和WES
测量.基因分型和WES将作为一种具有成本效益的分析方法进行
提出了我们将检查GC诱导的OHTN作为IOP变化的定量特征,
基线IOP和二分特征(GC应答者vs.无应答者)。我们将执行全基因组
关联和WES分析以及针对性分析。我们将针对基因中的变异,
在Aim 1、GRES基因座和先前相关的基因中,
眼压或开角型青光眼我们将使用以下方法研究同一基因座的罕见变异与疾病结局的关系:
骨料和配料试验。我们将招募一个530名参与者的复制队列,
测序,以跟进发现分析中的提示性或重要发现。我们还将在
在三个外部队列中用现有的基因组数据对这些发现进行计算机复制。含义:如果基因
与GC诱导的IOP升高相关,它们不仅将提供对这种并发症的深入了解,
病理生理学,而且更广泛地进入POAG机制。我们的发现将对临床
管理GC患者。如果我们能够识别有GC诱导OHTN风险的患者,
使用替代疗法或增加监测,而患者接受GC的发病率。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lucia Sobrin其他文献
Lucia Sobrin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Lucia Sobrin', 18)}}的其他基金
Elucidating novel mechanisms for glucocorticoid-induced ocular hypertension
阐明糖皮质激素诱发高眼压的新机制
- 批准号:
10542404 - 财政年份:2020
- 资助金额:
$ 78.19万 - 项目类别:
Multi-ethnic GWAS of diabetic retinopathy: enhanced power using new methods
糖尿病视网膜病变的多种族 GWAS:使用新方法增强功效
- 批准号:
8528611 - 财政年份:2012
- 资助金额:
$ 78.19万 - 项目类别:
Multi-ethnic GWAS of diabetic retinopathy: enhanced power using new methods
糖尿病视网膜病变的多种族 GWAS:使用新方法增强功效
- 批准号:
8264888 - 财政年份:2012
- 资助金额:
$ 78.19万 - 项目类别:
相似海外基金
The effects of remifentanil on volatile anesthetics-induced myocardial protection and antiinflammatory effect
瑞芬太尼对挥发性麻醉药所致心肌保护及抗炎作用的影响
- 批准号:
25462404 - 财政年份:2013
- 资助金额:
$ 78.19万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
COMPARISON OF CLINICAL BENEFIT, ANTIINFLAMMATORY EFFECT
临床疗效、抗炎作用比较
- 批准号:
6504473 - 财政年份:2000
- 资助金额:
$ 78.19万 - 项目类别:
COMPARISON OF CLINICAL BENEFIT, ANTIINFLAMMATORY EFFECT
临床疗效、抗炎作用比较
- 批准号:
6566325 - 财政年份:2000
- 资助金额:
$ 78.19万 - 项目类别:
COMPARISON OF CLINICAL BENEFIT, ANTIINFLAMMATORY EFFECT
临床疗效、抗炎作用比较
- 批准号:
6304293 - 财政年份:1999
- 资助金额:
$ 78.19万 - 项目类别:
COMPARISON OF CLINICAL BENEFIT, ANTIINFLAMMATORY EFFECT
临床疗效、抗炎作用比较
- 批准号:
6114208 - 财政年份:1998
- 资助金额:
$ 78.19万 - 项目类别:
COMPARISON OF CLINICAL BENEFIT, ANTIINFLAMMATORY EFFECT
临床疗效、抗炎作用比较
- 批准号:
6275443 - 财政年份:1997
- 资助金额:
$ 78.19万 - 项目类别: