Identifying Contributions of Pulmonary Inflammation to Sleep-Disordered Breathing
确定肺部炎症对睡眠呼吸障碍的影响
基本信息
- 批准号:10064441
- 负责人:
- 金额:$ 8.95万
- 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:2020-09-05 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:ANGPT2 geneANXA2 geneAdultAffectAnimalsBindingBiologicalBiological AssayBiological MarkersCAV1 geneCarbon MonoxideCardiopulmonaryCell LineChronicCohort StudiesContinuous Positive Airway PressureDLEC1 geneDataDevelopmentDiffuseDiseaseEpigenetic ProcessFramingham Heart StudyFrequenciesFutureGene ExpressionGenesGeneticGenetic studyGenomeGenotype-Tissue Expression ProjectGoalsHumanHypoxemiaIL18 geneImageImmuneIndividualInflammasomeInflammationInjuryInterstitial Lung DiseasesJointsLeadLeukocytesLiteratureLungLung InflammationLung diseasesMeasuresMediatingMetabolicModelingMolecularMulti-Ethnic Study of AtherosclerosisMultivariate AnalysisMusNRG1 geneNational Heart, Lung, and Blood InstituteParticipantPathogenesisPathway interactionsPatientsPhenotypePhysiologicalPulmonary FibrosisPulmonary InflammationRiskRoleSeveritiesSleepSleep Apnea SyndromesSpirometryTestingThickTissuesTrans-Omics for Precision MedicineTranslatingVariantWorkX-Ray Computed Tomographyalveolar destructionalveolar epitheliumcausal variantcell typecirculating biomarkerscommon treatmentcompliance behaviorcytokineepithelial injurygenetic associationgenome sequencinggenome wide association studygenomic locusidiopathic pulmonary fibrosisimprovedinsightinterstitiallung imaginglung injurymonocytenoveloverexpressionpersonalized medicinepolygenic risk scoreprogramsstatisticssuccesstraittranscription factorwhole genomeworking group
项目摘要
ABSTRACT
Sleep disordered breathing (SDB), which includes sleep apnea and related disorders, is a highly prevalent
disorder that increases the risk of cardiopulmonary, metabolic, and other diseases. Continuous positive airway
pressure (CPAP), the most common treatment for SDB, remains suboptimal with poor patient adherence.
Identifying genes contributing to physiologically relevant pathways will increase our understanding and aid in
the discovery of improved countermeasures and more personalized treatments. As part of the PI’s ongoing K01
project, we assembled the largest known genetic study of objectively measured SDB and identified the first
common- and rare-frequency genetic associations with SDB at genome-level significance. Literature searches
indicate that many of our suspected genes in multiple associated regions are involved with pulmonary
inflammation, suggesting that genes implicated in pulmonary inflammation may have an important but
unmeasured causal role for the development of SDB (in addition to the known effects of SDB on inflammation).
Simultaneously, our collaborators have identified associations between SDB and subclinical measures of
interstitial lung disease defined by abnormalities in computed tomography images. SDB affects up to 88% of
adults with idiopathic pulmonary fibrosis (IPF), and many of our suspected SDB genes are also implicated in
IPF. The broad overlap of these genes suggests that pulmonary inflammation and injury may contribute to SDB
through a common biological mechanism. The next logical steps in translating these genetic findings into
broader biological insights are to systematically investigate the impact of inflammation on SDB and clarify if
these potential effects are mediated by pulmonary or other effects. Candidate traits that influence SDB will be
identified using polygenic risk scores derived from existing studies. The potential impact of these significant
traits at specific genetic loci will be investigated using genetic colocalization. We will also identify genes that
may be mediating these interactions using externally derived gene expression data in candidate tissues. Our
specific aims are to: 1) to identify potential inflammation-related predictors of sleep disordered breathing
severity; and 2) to identify potential pulmonary predictors of sleep disordered breathing severity. The proposed
project is a natural extension of the PI’s K01 and will improve our understanding of the potential physiological
and molecular mechanisms of sleep disordered breathing, a common disorder impacting millions of
individuals.
摘要
睡眠呼吸障碍(SDB),包括睡眠呼吸暂停和相关疾病,是一种非常普遍的疾病。
增加心肺、代谢和其他疾病风险的疾病。持续气道
压力(CPAP)是最常见的睡眠呼吸暂停综合症治疗方法,但由于患者依从性较差,仍然不理想。
识别有助于生理相关途径的基因将增加我们对基因表达的理解和帮助。
发现改进的对策和更个性化的治疗方法。作为PI持续K 01的一部分
项目,我们收集了最大的已知的客观测量SDB的遗传研究,并确定了第一个
在基因组水平显著性上与SDB存在常见和罕见的遗传关联。文献检索
这表明我们在多个相关区域的许多疑似基因都与肺部疾病有关,
炎症,这表明与肺部炎症有关的基因可能具有重要的作用,但
SDB发展的不可测量的因果作用(除了SDB对炎症的已知作用之外)。
同时,我们的合作者已经确定了SDB和亚临床指标之间的关联,
由计算机断层扫描图像异常定义的间质性肺病。SDB影响高达88%的
成人特发性肺纤维化(IPF),我们怀疑的许多SDB基因也与
IPF。这些基因的广泛重叠表明肺部炎症和损伤可能导致SDB
通过一个共同的生物机制。将这些基因发现转化为
更广泛的生物学见解是系统地研究炎症对SDB的影响,并阐明
这些潜在的影响是由肺部或其他影响介导的。影响SDB的候选性状将是
使用来自现有研究的多基因风险评分进行识别。这些重大的潜在影响
将使用遗传共定位研究特定遗传基因座的性状。我们还将鉴定出
可能是使用候选组织中外部来源的基因表达数据来介导这些相互作用。我们
具体目标是:1)识别与炎症相关的潜在睡眠呼吸障碍预测因子
严重程度;和2)识别睡眠呼吸障碍严重程度的潜在肺部预测因子。拟议
项目是PI K 01的自然延伸,将提高我们对潜在生理学的理解。
和睡眠呼吸障碍的分子机制,这是一种影响数百万人的常见疾病,
个体
项目成果
期刊论文数量(0)
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Brian Edmand Cade其他文献
Brian Edmand Cade的其他文献
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{{ truncateString('Brian Edmand Cade', 18)}}的其他基金
Genetic Epidemiology of Sleep Apnea and Comorbidities in Biobanks
生物样本库中睡眠呼吸暂停和合并症的遗传流行病学
- 批准号:
10211082 - 财政年份:2021
- 资助金额:
$ 8.95万 - 项目类别:
Genetic Epidemiology of Sleep Apnea and Comorbidities in Biobanks
生物样本库中睡眠呼吸暂停和合并症的遗传流行病学
- 批准号:
10670187 - 财政年份:2021
- 资助金额:
$ 8.95万 - 项目类别:
Genetic Epidemiology of Sleep Apnea and Comorbidities in Biobanks
生物样本库中睡眠呼吸暂停和合并症的遗传流行病学
- 批准号:
10470170 - 财政年份:2021
- 资助金额:
$ 8.95万 - 项目类别:
Identifying Contributions of Pulmonary Inflammation to Sleep-Disordered Breathing
确定肺部炎症对睡眠呼吸障碍的影响
- 批准号:
10254316 - 财政年份:2020
- 资助金额:
$ 8.95万 - 项目类别:
Whole Genomic Characterization of Sleep Apnea Traits and Comorbid Disorders
睡眠呼吸暂停特征和共病疾病的全基因组特征
- 批准号:
9224502 - 财政年份:2017
- 资助金额:
$ 8.95万 - 项目类别:
Whole Genomic Characterization of Sleep Apnea Traits and Comorbid Disorders
睡眠呼吸暂停特征和共病疾病的全基因组特征
- 批准号:
9926089 - 财政年份:2017
- 资助金额:
$ 8.95万 - 项目类别: