Mechanisms Regulating Vascular Homeostasis
Mechanisms Regulating Vascular Homeostasis
批准号:
10475687
负责人:
Christopher D Kontos
金额:
$52.67万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-01 至 2025-07-31
关键词:
ANGPT1 geneAddressAdhesionsAngiopoietinsApolipoprotein EAtherosclerosisBindingBinding SitesBiologyBlood VesselsCRISPR/Cas technologyCalmodulinCardiovascular DiseasesCell SurvivalCell physiologyCessation of lifeCo-ImmunoprecipitationsCoronary heart diseaseDefectEndothelial CellsEndotheliumEventGene ExpressionGeneticGenetic TranscriptionGoalsHealthHomeostasisHypertensionIn VitroInflammationLeadLigandsLinkLiquid substanceMalignant NeoplasmsMediatingModelingMolecularMusMyographyNOS3 geneNitric OxideOxygenPathologic NeovascularizationPerfusionPermeabilityPhenotypePhosphorylationPlayProteinsPublic HealthReceptor SignalingRecombinant ProteinsRegulationRegulatory PathwayRetinal DiseasesRoleScaffolding ProteinSeptic ShockSignal PathwaySignal TransductionTestingTranscription Factor AP-1Vascular DiseasesVascular PermeabilitiesVascular remodelingangiogenesisatheroprotectivebasecardiovascular disorder preventiondensityendothelial dysfunctionhypertensivein vivoinduced pluripotent stem cellloss of functionmonocytemutantnovelpressurepreventreceptorresponserhoshear stresstranscription factorvascular inflammationwestern diet
中文摘要
项目概要
正常内皮细胞 (EC) 功能的调节在血管稳态和
预防心血管疾病(CVD)。 CVD 中的内皮功能障碍的特点是丧失
内皮一氧化氮合酶(eNOS)衍生的一氧化氮(NO)。 Tie 受体及其配体
血管生成素 (Ang) 是血管稳态和 EC 静止状态转变的重要调节剂
到“激活”和血管重塑。鉴于 Ang-1/Tie2 信号传导促进 EC 存活和静止,
同源 Tie1 受体部分通过 Akt 和 eNOS 的激活来促进 EC
活化、炎症和动脉粥样硬化。然而,Tie1 也是 Tie2 介导的血管生成所必需的,
Tie1 的整体功能效果似乎与环境相关,并且部分与以下因素的存在相关:
炎症。与 Tie2 不同,Tie1 没有已知的激活配体,因此其信号通路和
行动机制很难研究,而且仍然知之甚少。我们确定了一本小说
先前未表征的分子支架蛋白 Caskin2,作为 Tie1 相互作用蛋白。虽然很少
研究专门探讨了 Caskin2 的功能,它已被确定为 EC 的强有力标志物,并且
许多分子研究已将 Caskin2 与血管缺陷相关的表型联系起来。
体内平衡。重要的是,我们的研究表明 Caskin2 是 Tie 受体之间的关键分子连接
信号传导、eNOS 生物学和血管稳态。我们对该提案的初步研究表明
Caskin2 在体外和体内的 EC 中高表达,Caskin2 促进 EC 静止和存活
体外。 Caskin2 与 Tie1 的结合被 Tie1 上 T794 的磷酸化破坏,该事件由
PAK 以 Rac 依赖性方式存在,这是血管生成所必需的。此外,Caskin2 是 Ang- 所必需的。
1/Tie2 通过 Akt 介导的信号传导,表明 Caskin2 整合了来自 Tie1 和 Tie2 的信号
调节血管稳态。此外,Caskin2 结合 eNOS 及其激活剂钙调蛋白 (CaM),
增加 eNOS 表达和活性,并通过流体剪切应力和 KLF2 上调。最后,我们
表明 Caskin2–/– 小鼠血管通透性增加、动脉粥样硬化、病理性血管生成、
和高血压,所有以异常 eNOS 信号传导为特征的血管稳态疾病。基于
根据这些发现,我们假设 Caskin2 是 Tie 受体信号传导的关键整合者
部分通过 eNOS 激活调节血管稳态。为了检验这一假设,具体
该提案的目的是: 1) 确定 Caskin2 调节 Tie 的分子机制
受体介导的内皮功能和 eNOS 活性; 2) 确定 Caskin2 的机制
响应并感知流体剪切应力的变化,以在体外调节 EC 表型; 3) 确定
Caskin2 缺陷对体内血管稳态的影响。
英文摘要
PROJECT SUMMARY
Regulation of normal endothelial cell (EC) function plays a critical role in vascular homeostasis and the
prevention of cardiovascular disease (CVD). Endothelial dysfunction in CVD is characterized by loss of
endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO). The Tie receptors and their ligands, the
angiopoietins (Ang), are important regulators of vascular homeostasis and the transition from EC quiescence
to "activation" and vascular remodeling. Whereas Ang-1/Tie2 signaling promotes EC survival and quiescence,
in part through activation of Akt and eNOS, the homologous Tie1 receptor has been shown to promote EC
activation, inflammation, and atherosclerosis. However, Tie1 is also required for Tie2-mediated angiogenesis,
and Tie1's overall functional effects appear to be context-dependent and linked, in part, to the presence of
inflammation. Unlike Tie2, Tie1 has no known activating ligands, therefore its signaling pathways and
mechanisms of action have been difficult to study and remain poorly understood. We identified a novel and
previously uncharacterized molecular scaffolding protein, Caskin2, as a Tie1-interacting protein. Although few
studies have specifically addressed Caskin2's function, it has been identified as a strong marker of ECs, and
numerous molecular studies have linked Caskin2 to phenotypes associated with defects in vascular
homeostasis. Importantly, our studies indicate that Caskin2 is a critical molecular link between Tie receptor
signaling, eNOS biology, and vascular homeostasis. Our preliminary studies in this proposal demonstrate that
Caskin2 is highly expressed in ECs in vitro and in vivo and that Caskin2 promotes EC quiescence and survival
in vitro. Caskin2 binding to Tie1 is disrupted by phosphorylation of T794 on Tie1, an event that is mediated by
PAK in a Rac-dependent manner and that is required for angiogenesis. Moreover, Caskin2 is required for Ang-
1/Tie2-mediated signaling through Akt, suggesting that Caskin2 integrates signals from both Tie1 and Tie2 to
regulate vascular homeostasis. Furthermore, Caskin2 binds eNOS and its activator calmodulin (CaM) and
increases eNOS expression and activity and is upregulated by fluid shear stress and by KLF2. Finally, we
show that Caskin2–/– mice have increased vascular permeability, atherosclerosis, pathological angiogenesis,
and are hypertensive, all disorders of vascular homeostasis characterized by abnormal eNOS signaling. Based
on these findings, we hypothesize that Caskin2 is a critical integrator of Tie receptor signaling that
regulates vascular homeostasis in part through eNOS activation. To test this hypothesis, the Specific
Aims of this proposal are to: 1) Determine the molecular mechanisms by which Caskin2 regulates Tie
receptor-mediated endothelial function and eNOS activity; 2) Determine the mechanisms by which Caskin2
responds to and senses changes in fluid shear stress to regulate EC phenotypes in vitro; and 3) Determine the
effects of Caskin2 deficiency on vascular homeostasis in vivo.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Medical Scientist Training Program Training Grant
-
批准号:10411303
-
项目类别:
-
资助金额:$125.48万
-
财政年份:2022
-
负责人:Christopher D Kontos
-
依托单位:
Medical Scientist Training Program Training Grant
-
批准号:10647684
-
项目类别:
-
资助金额:$127.72万
-
财政年份:2022
-
负责人:Christopher D Kontos
-
依托单位:
Mechanisms Regulating Vascular Homeostasis
-
批准号:10299286
-
项目类别:
-
资助金额:$59.09万
-
财政年份:2021
-
负责人:Christopher D Kontos
-
依托单位:
Mechanisms Regulating Vascular Homeostasis
-
批准号:10666528
-
项目类别:
-
资助金额:$52.67万
-
财政年份:2021
-
负责人:Christopher D Kontos
-
依托单位:
TIE2 Activation for the Treatment of Chemical-Induced Acute Lung Injury
-
批准号:9753248
-
项目类别:
-
资助金额:$44.67万
-
财政年份:2017
-
负责人:Christopher D Kontos
-
依托单位:
TIE2 Activation for the Treatment of Chemical-Induced Acute Lung Injury
-
批准号:9352549
-
项目类别:
-
资助金额:$46.2万
-
财政年份:2017
-
负责人:Christopher D Kontos
-
依托单位:
Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease
-
批准号:9335975
-
项目类别:
-
资助金额:$45.0万
-
财政年份:2015
-
负责人:Christopher D Kontos
-
依托单位:
Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease
-
批准号:8887762
-
项目类别:
-
资助金额:$42.98万
-
财政年份:2015
-
负责人:Christopher D Kontos
-
依托单位:
Skeletal Muscle and Vascular Remodeling in Peripheral Artery Disease
-
批准号:8903576
-
项目类别:
-
资助金额:$51.64万
-
财政年份:2014
-
负责人:Christopher D Kontos
-
依托单位:
Muscle-Resident Stem Cells for Angiogenesis and Vascular Maturation in PAD
-
批准号:8707552
-
项目类别:
-
资助金额:$18.75万
-
财政年份:2013
-
负责人:Christopher D Kontos
-
依托单位:
Tie2 Activation for the Treatment of Chemical-Induced Acute Lung Injury
-
批准号:8743208
-
项目类别:
-
资助金额:$39.25万
-
财政年份:2013
-
负责人:Christopher D Kontos
-
依托单位:
Muscle-Resident Stem Cells for Angiogenesis and Vascular Maturation in PAD
-
批准号:8492528
-
项目类别:
-
资助金额:$21.96万
-
财政年份:2013
-
负责人:Christopher D Kontos
-
依托单位:
Tie2 Activation for the Treatment of Chemical-Induced Acute Lung Injury
-
批准号:8609927
-
项目类别:
-
资助金额:$37.83万
-
财政年份:2013
-
负责人:Christopher D Kontos
-
依托单位:
PTEN Gene Therapy for Vein Graft Disease
-
批准号:7634945
-
项目类别:
-
资助金额:$23.4万
-
财政年份:2009
-
负责人:Christopher D Kontos
-
依托单位:
PTEN Gene Therapy for Vein Graft Disease
-
批准号:7846252
-
项目类别:
-
资助金额:$19.5万
-
财政年份:2009
-
负责人:Christopher D Kontos
-
依托单位:
The Role of PTEN in Endothelial Biology
-
批准号:7851908
-
项目类别:
-
资助金额:$2.32万
-
财政年份:2008
-
负责人:Christopher D Kontos
-
依托单位:
The Role of PTEN in Endothelial Biology
-
批准号:7374082
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2008
-
负责人:Christopher D Kontos
-
依托单位:
The Role of PTEN in Endothelial Biology
-
批准号:7569421
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2008
-
负责人:Christopher D Kontos
-
依托单位:
The Role of PTEN in Endothelial Biology
-
批准号:7763912
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2008
-
负责人:Christopher D Kontos
-
依托单位:
Effects of the Angiopoietins on Tie 2 Downregulation
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批准号:6951066
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项目类别:
-
资助金额:$19.25万
-
财政年份:2004
-
负责人:Christopher D Kontos
-
依托单位:
海外基金