Molecular predictors of cardiovascular events and resilience in chronic coronary artery disease
心血管事件的分子预测因素和慢性冠状动脉疾病的恢复力
基本信息
- 批准号:10736587
- 负责人:
- 金额:$ 77.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAlgorithmsAmericanApoptosisAreaBiologicalBiological MarkersCardiovascular DiseasesCardiovascular systemCaringCessation of lifeChronicClinicalCohort StudiesCollaborationsCoronary AngiographyCoronary ArteriosclerosisDataDevelopmentDiseaseEventFatty AcidsFutureGDF15 geneGenesGeneticGoalsHeterogeneityInflammationInflammatoryInjuryInterferonsIschemiaKnowledgeLipolysisLongevityModelingMolecularMolecular TargetMuscle CellsMyocardial InfarctionNational Heart, Lung, and Blood InstituteOutcomeParticipantPathway interactionsPatientsPerformancePhenotypePopulationPreventionProbabilityProviderPublic HealthQuality of lifeResearchResidual stateRiskRisk AssessmentRisk FactorsSeveritiesSeverity of illnessSignal PathwaySignal TransductionTestingTimeTrans-Omics for Precision MedicineTranscriptTroponinValidationadipokinesadjudicationbiomarker identificationbiomarker performancecandidate markercandidate validationcardiovascular risk factorclinical riskcohortdifferential expressiondisorder riskfatty acid metabolismfatty acid oxidationhigh riskimprovedimproved outcomeinnovationmolecular modelingmultiple omicsnovelnovel markerpatient populationpersonalized risk predictionpolygenic risk scorepredictive modelingpreventpro-brain natriuretic peptide (1-76)programspromote resilienceprotective factorsresearch clinical testingresilienceresilience factorrisk predictionrisk stratificationtranscriptometranscriptomics
项目摘要
PROJECT ABSTRACT
State-of-the-art risk assessments in chronic coronary artery disease (CAD) only partially capture risk for
cardiovascular events (CVEs), leaving substantial ‘residual risk’ unaddressed. Current risk assessments also
incompletely capture resilience to CAD, defined as those at high risk by contemporary algorithms—but without
disease. This ‘residual protection’ highlights novel resiliency factors protective against the development of
CAD. In this context, it is crucial to understand factors related to both residual risk and resiliency to personalize
risk prediction and help clinicians and patients make better treatment decisions. Our overarching hypothesis
is that a multi ‘omics’ approach can identify molecular features of residual risk and resilience in CAD.
Historically, omics studies of CAD were limited by 1) phenotypic heterogeneity—reliance on variable definitions
of CAD and CVEs, biasing results and limiting prediction; and 2) risk homogeneity—constraining identification
of novel pathways and limiting generalizability. We overcome these limitations by leveraging unique access to
landmark NHLBI CAD strategy trials and a cohort study with aligned core-lab confirmed testing, molecular
data, and adjudicated CVEs. Collectively, these studies span the CAD risk continuum—a feature critical to
assessing performance of biomarkers and molecular features and overcoming prior limitations. Preliminary
data supporting our hypothesis show: 1) substantial, unexplained residual risk (>30%) for death/myocardial
infarction with a clinical model of risk factors and CAD severity, 2) biomarkers of inflammation, myocyte injury
and distension improve model performance, and 3) novel transcriptome modules of inflammation and
interferon signaling further improve prediction. New preliminary data from the imputed transcriptome of
‘resilient’ patients without CAD demonstrates dysregulated pathways and genes of fatty acid metabolism. Our
overall goal is to leverage well-phenotyped participants from these landmark studies to improve CVE
prediction and better understand resilience to CAD. We propose the following specific aims. Aim 1: Improve
prediction of CVEs in patients with established CAD. We will test and validate (1a) candidate biomarkers,
polygenic risk scores for CAD and (1b) transcriptomics to improve CVE prediction beyond a clinical model of
risk factors and state-of-the-art testing (core-lab confirmed severity of CAD and ischemia). Aim 2: Identify
biomarkers and molecular features of resilience to CAD. We will test the association of (2a) candidate
biomarkers and (2b) transcriptomics among resilient patients without CAD despite a high probability of disease
by clinical and polygenic risk scores for CAD. In the applicant’s opinion, this proposal is innovative and departs
from the status quo by using meticulously adjudicated CVEs and phenotype from patients across the CAD risk
spectrum and is significant because it will accelerate personalized risk stratification and treatment—especially
for the large number of patients at intermediate risk for CAD and CVEs. Ultimately, knowledge generated from
this application has the potential to improve the care and outcomes for millions of Americans with CAD.
项目摘要
慢性冠状动脉疾病(CAD)的最新风险评估仅部分捕获以下风险:
心血管事件(CVEs),留下大量的“剩余风险”未得到解决。目前的风险评估还
不完全捕获对CAD的弹性,现代算法将其定义为高风险,但没有
疾病这种“剩余保护”突出了新的弹性因素,
CAD.在这种情况下,了解与剩余风险和弹性相关的因素,
风险预测,帮助临床医生和患者做出更好的治疗决策。我们的首要假设是
多组学方法可以识别CAD中剩余风险和恢复力的分子特征。
从历史上看,CAD的组学研究受到以下限制:1)表型异质性-依赖于变量定义
CAD和CVE的偏差结果和限制预测;以及2)风险可行性约束识别
新的途径和有限的普遍性。我们通过利用独特的访问权限来克服这些限制,
具有里程碑意义的NHLBI CAD策略试验和一项队列研究,包括经对齐的核心实验室确认的检测、分子
数据和裁定的CVE。总的来说,这些研究涵盖了CAD风险连续性,这是
评估生物标志物和分子特征的性能并克服先前的限制。初步
支持我们假设的数据显示:1)死亡/心肌梗死的大量、无法解释的剩余风险(>30%)
梗死与危险因素和CAD严重程度的临床模型,2)炎症、肌细胞损伤的生物标志物
和扩张改善模型性能,和3)炎症和炎症的新转录组模块,
干扰素信号传导进一步改善预测。来自插补转录组的新初步数据
没有CAD的“有弹性”患者表现出脂肪酸代谢途径和基因失调。我们
总体目标是利用这些具有里程碑意义的研究中表型良好的参与者来改善CVE
预测和更好地了解CAD的弹性。我们提出以下具体目标。目标1:改善
预测确诊CAD患者的心血管事件。我们将测试和验证(1a)候选生物标志物,
CAD的多基因风险评分和(1b)转录组学,以改善CVE预测超过临床模型,
风险因素和最先进的检测(核心实验室确认的CAD和缺血严重程度)。目标2:确定
生物标志物和分子特征的恢复CAD。我们将测试(2a)候选项的关联
生物标志物和(2b)无CAD的弹性患者中的转录组学,尽管疾病的可能性很高
冠心病的临床和多基因风险评分。申请人认为,该提案具有创新性,
通过使用来自CAD风险患者的精心裁定的CVE和表型,
它的意义在于,它将加速个性化的风险分层和治疗,
对于大量处于CAD和CVE中等风险的患者。最终,知识产生于
该应用具有改善数百万患有CAD的美国人的护理和结果的潜力。
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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JONATHAN D NEWMAN其他文献
JONATHAN D NEWMAN的其他文献
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{{ truncateString('JONATHAN D NEWMAN', 18)}}的其他基金
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- 批准号:
10638946 - 财政年份:2023
- 资助金额:
$ 77.75万 - 项目类别:
Molecular predictors of resistance and vulnerability to cardiovascular events in stable ischemic heart disease
稳定型缺血性心脏病中心血管事件抵抗力和易感性的分子预测因子
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