Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
基本信息
- 批准号:7624276
- 负责人:
- 金额:$ 34.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-01 至 2011-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcetatesAcuteApolipoprotein EArterial Fatty StreakAtherosclerosisBacterial InfectionsBindingBiological AssayCardiovascular DiseasesCarotid ArteriesCell Differentiation processCellsChronic DiseaseClinicalComplexCouplingCytokine GeneDeveloped CountriesDeveloping CountriesDevelopmentDiseaseDoctor of PhilosophyDrug Delivery SystemsElectrophoretic Mobility Shift AssayEpidemiologic StudiesExpression LibraryFamilyFoundationsGelatinase BGene ExpressionGene-ModifiedGenesGeneticGenetic TranscriptionGoalsHL60HyperplasiaIndiumInflammationInflammatoryInterferonsKnockout MiceLesionLifeLipidsLipoproteinsLuciferasesMLLT7 geneMalignant NeoplasmsMediatingModelingMolecularMultiple SclerosisMusMyocardial InfarctionNeoplasm MetastasisOxidative StressPIM1 genePathogenesisPatientsPharmaceutical PreparationsPhenotypePhosphotransferasesPlayProductionReporterResearch PersonnelRheumatoid ArthritisRoleRuptureScreening procedureSepsisSignal PathwaySignal TransductionSmooth Muscle MyocytesStrokeSystemT-LymphocyteTestingTherapeutic InterventionThrombosisTranscriptional ActivationUp-RegulationatherogenesiscDNA Expressioncytokinedesignextracellularforkhead proteinhuman diseasein vivoinjuredmacrophagemembermonocytemortalitynew therapeutic targetnovelphorbol-12-myristateprogramspromoterresearch studyresponsestress-activated protein kinase 1toll-like receptor 4
项目摘要
DESCRIPTION (provided by applicant): Complications of atherosclerosis are the leading cause of mortality in developed countries. More than 100 genes that can influence atherogenesis have been identified. Our long-term goals are to elucidate the signaling dependent transcriptional mechanisms of these genes. Recently, we identified a novel transcriptional mechanism by which FOXO4 regulates smooth muscle cell (SMC) phenotypes and transcription of matrix metalloproteinase 9 (MMP9) and Toll-like-receptor 4 (TLR4). As SMC phenotypic modulation, MMP9, and TLR4 are involved in atherogenesis, we propose that FOXO4 contributes to atherosclerosis through these effectors. Three specific aims are proposed. (1) To characterize the signaling pathways that regulate FOXO4 activities. We will investigate whether FOXO4 mediates JNK-activated MMP9 transcription and whether JAK/STAT signaling suppresses MMP9 transcription through inactivation of FOXO4 by PIM kinases. (2) To investigate the role of FOXO4 in transcriptional activation of TLR4. We will study the molecular mechanism by which FOXO4 activates TLR transcription and examine whether upregulation of TLR4 by FOXO4 is sufficient to promote TLR4-mediated proinflammatory cytokine production. We will also investigate whether FOXO4 plays a role during monocyte to macrophage differentiation. (3) To determine whether and how FOXO4 promotes atherosclerosis. We will test whether inactivation of Foxo4 in apoE-null mice reduces atherosclerosis and whether Foxo4 influences atherosclerosis through downstream effectors (TLR4, MMP9), and/or SMC phenotypic modulation. The lack of response to lipid-lowering drugs in patients with cardiovascular disease emphasizes the need to identify new therapeutic targets for the treatment of atherosclerosis. FOXO4 is a promising target for therapeutic intervention since inhibition of FOXO4 activity may reduce TLR4-induced cytokine production, reduce intimal thickening, and stabilize late atherosclerotic plaques. Accomplishing the specific aims in this proposal will provide the foundation to assess this possibility. While our focus in this proposal is to understand the role of FOXO4 in atherosclerosis, studies of the specific aims 1 & 2 will also help us to understand the role of FOXO4 in other human diseases such as rheumatoid arthritis, multiple sclerosis, and cancer, as MMP9 and/or TLR4 are implicated in the pathogenesis of these diseases as well.
描述(申请人提供):动脉粥样硬化并发症是发达国家死亡的主要原因。目前已鉴定出100多个影响动脉粥样硬化形成的基因。我们的长期目标是阐明这些基因依赖于信号的转录机制。最近,我们发现了一种新的转录机制,通过FOXO4调节平滑肌细胞(SMC)表型和基质金属蛋白酶9(MMP9)和Toll样受体4(TLR4)的转录。由于SMC表型调节、MMP9和TLR4参与了动脉粥样硬化的形成,我们认为FOXO4通过这些效应分子参与动脉粥样硬化的形成。提出了三个具体目标。(1)研究调控FOXO4活性的信号通路。我们将研究FOXO4是否介导JNK激活的MMP9转录,以及JAK/STAT信号是否通过PIM激酶失活FOXO4来抑制MMP9转录。(2)探讨FOXO4在TLR4转录激活中的作用。我们将研究FOXO4激活TLR转录的分子机制,并检验FOXO4上调TLR4是否足以促进TLR4介导的促炎细胞因子的产生。我们还将研究FOXO4是否在单核细胞向巨噬细胞分化过程中发挥作用。(3)确定FOXO4是否促进动脉粥样硬化以及如何促进动脉粥样硬化。我们将测试在apoE缺失小鼠中灭活FOXO4是否可以减少动脉粥样硬化,以及FOXO4是否通过下游效应因子(TLR4,MMP9)和/或SMC表型调节影响动脉粥样硬化。心血管疾病患者对降脂药物缺乏反应,强调了确定治疗动脉粥样硬化的新靶点的必要性。FOXO4是一个有希望的治疗干预靶点,因为抑制FOXO4活性可以减少TLR4诱导的细胞因子的产生,减少内膜增厚,并稳定晚期动脉粥样硬化斑块。实现这项提案中的具体目标将为评估这一可能性提供基础。虽然我们的重点是了解FOXO4在动脉粥样硬化中的作用,但对特定目标1和2的研究也将帮助我们了解FOXO4在其他人类疾病中的作用,如类风湿性关节炎、多发性硬化症和癌症,因为MMP9和/或TLR4也与这些疾病的发病机制有关。
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 }}
Zhi-Ping Liu其他文献
Zhi-Ping Liu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('Zhi-Ping Liu', 18)}}的其他基金
Role of Cilp1 in Post-Natal Heart Response to Injury
Cilp1 在产后心脏损伤反应中的作用
- 批准号:
10580830 - 财政年份:2022
- 资助金额:
$ 34.3万 - 项目类别:
Role of Cilp1 in Post-Natal Heart Response to Injury
Cilp1 在产后心脏损伤反应中的作用
- 批准号:
10365053 - 财政年份:2022
- 资助金额:
$ 34.3万 - 项目类别:
Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
心脏肥大和心力衰竭的表观遗传调控
- 批准号:
8511805 - 财政年份:2012
- 资助金额:
$ 34.3万 - 项目类别:
Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
心脏肥大和心力衰竭的表观遗传调控
- 批准号:
8656758 - 财政年份:2012
- 资助金额:
$ 34.3万 - 项目类别:
Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
心脏肥大和心力衰竭的表观遗传调控
- 批准号:
8371213 - 财政年份:2012
- 资助金额:
$ 34.3万 - 项目类别:
相似海外基金
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 34.3万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 34.3万 - 项目类别:
Standard Grant