Alterations in Unbound Free Fatty Acid Profiles in CVD
CVD 中未结合游离脂肪酸谱的变化
基本信息
- 批准号:10761556
- 负责人:
- 金额:$ 29.3万
- 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:2023-08-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffinityAlbuminsAngiotensin-Converting Enzyme InhibitorsBindingBiologicalBiological MarkersBloodBlood specimenCardiacCardiovascular DiseasesCardiovascular systemCellsCessation of lifeClinical DataDataDetectionDiseaseDissociationEquilibriumEventFemaleFluorescent ProbesFutureGoalsHumanIschemiaLipidsLiquid substanceMapsMeasurableMeasurementMeasuresMethodsMole the mammalMyocardial IschemiaNational Heart, Lung, and Blood InstituteNonesterified Fatty AcidsPatientsPercutaneous Transluminal Coronary AngioplastyPhasePhysiologicalPlasmaPredictive FactorPublishingROC CurveRecording of previous eventsReference StandardsReportingRiskRisk AssessmentRisk FactorsRoleSamplingSmall Business Innovation Research GrantSudden DeathSumadverse outcomeaqueouscomparison controlfatty acid metabolismimprovedimproved outcomeindexingindividual patientinhibitormalemetermortalitynew therapeutic targetnovelpalmitoleatepi bondprofiles in patientsprognosticprognostic valueprotein biomarkersrisk predictionrisk stratificationscreeningtherapeutic target
项目摘要
Project Summary- Patients with stable cardiovascular disease (CVD) have an elevated risk of
a second event. The easiest method for screening risk in stable CVD patients would use
biomarkers. However, no single marker has sufficient prognostic power. In this project we will
determine whether profiles of unbound free fatty acids (FFAu) can help predict the risk of
adverse outcomes in patients with stable cardiovascular disease (CVD). Plasma free fatty acids
(FFA) which are mostly bound to albumin have long been associated with cardiac ischemia.
Although present at only nM concentrations, the FFAu are the physiologically relevant fraction
because the unbound and not the bound are transported into cells. We developed fluorescent
probes (ADIFAB) to measure FFAu and found that FFAu levels were associated with
cardiovascular ischemia during PTCA and in patients with STEMI in TIMI II. Human plasma is
composed of about 30 unique FFA. Because they have distinct biological effects, we have
developed a method to determine the different FFAu (profiles). The NHLBI provided us with
plasma from 1200 patients (w/ clinical data) from the PEACE trial which sought to determine
whether ACE inhibitors would improve outcomes in patients who had a cardiovascular event.
We used our FFAu profiling method to profile 200 of the PEACE patients. For most of the FFAu
there were no significant case (event) vs. control (no event) differences. However, for unbound
alpha linolenate (αLNAu) the average case mole fractions were more than twice controls
(p<0.0002). ROC analysis of the αLNAu concentrations in the 200 FFAu profiles yielded a C-
index of 0.702, which is superior to the current 5 best biomarkers combined. This result
suggests that αLNAu might be a novel risk factor that reflects events orthogonal to the current
best biomarkers of stable CVD. Unexpectedly, two of the weakest binding FFAus, palmitoleate
(POAu) and linolenate (αLNAu) had “zero” unbound, although both were present bound to
albumin. Importantly, we found that blocking dissociation of POAu and α-LNAu occurs in blood
but does not occur in aqueous media composed of albumin and FFA. In our FFAu profiles of
healthy blood samples and non-cardiac diseases we found no measurable POAu and α-LNAu.
This implies that there are specific inhibitors of POA and α-LNA dissociation from albumin in
most blood samples, revealing a hitherto unknown mechanism for regulating FFA metabolism
and a potential therapeutic target. Thus, FFAu profiles reveal biological effects that are invisible
to total FFA profiles. In this project we will complete the measurement and analysis of the
remaining unanalyzed PEACE samples and begin the search for the inhibitor of release.
项目摘要-稳定性心血管疾病(CVD)患者的风险增加
第二个事件。对稳定的心血管疾病患者进行风险筛查最简单的方法是使用
生物标志物。然而,没有一个单一的标记物具有足够的预后能力。在这个项目中,我们将
确定游离脂肪酸(FFAu)的分布是否有助于预测糖尿病的风险
稳定性心血管疾病(CVD)患者的不良结局。血浆游离脂肪酸
长期以来,主要与白蛋白结合的游离脂肪酸(FFA)与心肌缺血有关。
虽然只存在NM浓度,但FFAU是生理上相关的部分
因为未绑定的和未绑定的被传输到细胞中。我们开发了荧光灯
用于测量FFAu的探针(ADIFAB),发现FFAu水平与
TIMI II中PTCA和STEMI患者的心血管缺血。
由大约30个独特的FFA组成。因为它们有不同的生物效应,我们有
开发了一种确定不同FFAU(轮廓)的方法。NHLBI为我们提供了
来自和平试验的1200名患者的血浆(有临床数据),该试验试图确定
血管紧张素转换酶抑制剂是否会改善心血管事件患者的预后。
我们使用我们的FFAU分析方法对200名PRESS患者进行了分析。对于大多数FFAU
病例(事件)与对照(无事件)之间没有显著差异。但是,对于未绑定的
α亚麻酸(αLNAu)病例平均摩尔分数是对照组的两倍多
(宝洁0.0002)。对200FFAU剖面中αLNAu浓度的ROC分析得出了C-
指数为0.702,优于目前最好的5个生物标志物的总和。这个结果
提示αLNAU可能是一个新的危险因素,反映了与当前事件垂直的事件
稳定性CVD的最佳生物标志物。出乎意料的是,两种结合能力最弱的FFAU,棕榈酸酯
(POAu)和亚麻酸(αLNAu)没有结合,尽管两者都存在结合
白蛋白。重要的是,我们发现POAu和α-LNAu在血液中发生了阻断解离
但在由白蛋白和FFA组成的水介质中不发生。在我们的FFAU配置文件中
健康血样和非心脏病患者未检测到POAu和α-LNAu。
这意味着在白蛋白中存在着POA和α-LNA解离的特异性抑制剂。
大多数血液样本,揭示了一种迄今未知的调节FFA代谢的机制
也是一个潜在的治疗靶点。因此,FFAU曲线揭示了看不见的生物效应
以总计FFA配置文件。在本项目中,我们将完成对数据的测量和分析
剩余的未分析的和平样品,并开始寻找释放的抑制物。
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 }}
Alan Kleinfeld其他文献
Alan Kleinfeld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 }}
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 29.3万 - 项目类别:
Continuing Grant