Membrane Raft Platforms in Inflammasome Activation and Endothelial Dysfunction

炎症小体激活和内皮功能障碍中的膜筏平台

基本信息

  • 批准号:
    9273595
  • 负责人:
  • 金额:
    $ 40.02万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-03-15 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Membrane raft (MR) (formerly lipid raft) in endothelial cell (EC) forms lysosomal-MR signaling platforms or signalosomes to regulate endothelial function and to be involved in endothelial dysfunction, vascular injury and atherogenesis. Over the lasting funding period, we have shown that the MR signaling platforms are associated with translocation of lysosomal acid sphingomyelinase (Asm) and local ceramide production. The present proposal has planned to extend the findings from cell and molecular approaches to animal disease models to address the physiological and pathological relevance of this endothelial MR signaling platform by using genetically-engineered animals. The major focus will be on its triggering role in the activation of nucleotide oligomerization domain-like receptor protein with pryin domain containing 3 (Nlrp3) and consequent endothelial damage and atherosclerotic lesions. The central hypothesis being tested is that Asm-ceramide signaling platforms mediate the activation of Nlrp3 inflammasomes in ECs at the early stage of hypercholesterolemia and thereby produces endothelial injury as a triggering mechanism to result in subsequent atherosclerotic lesions on the carotid arterial wall in concert with local inflammatory responses. To test this hypothesis, three Specific Aims are proposed. Specific aim 1 will determine whether endothelial Nlrp3 inflammasome activation associated with enhanced ceramide production contributes to carotid endothelial dysfunction or injury at the early stage of hypercholesterolemia and late atherosclerotic lesions in the carotid arteries using Asm-/- mice, endothelium-specific Asm transgenic mice (EC-Asmtrg), and their wild type (WT) littermates. Specific Aim 2 will explore the molecular mechanisms by which increased ceramide production activates Nlrp3 inflammasomes with a main focus on the formation of MR redox signalosomes, lysosome dysfunction and kinase suppressor of ras (KSR) as a scaffold in isolated carotid ECs from Asm-/-, EC-Asmtrg and WT mice. In Specific Aim 3, we attempt to determine how ceramide-mediated Nlrp3 inflammasome activation leads to endothelial dysfunction or injury by studying the role of activated caspase-1 and its products in impaired endothelium-dependent vasodilation (EDVD), pyroptosis, altered expression of adhesion and junction proteins, and adaptive endothelial progenitor cells (EPCs) landing or differentiation. To our knowledge, these proposed studies will be the first to investigate the contribution of MR signaling platforms to the activation of Nlrp3 inflammasomes in EC, thereby leading to endothelial dysfunction and consequent atherosclerotic lesion in the arterial wall. The findings of Nlrp3 inflammasome activation to produce both classical inflammatory response and uncanonical vascular injury may shift the paradigm in how we understand the role of inflammation in atherogenesis and cardiovascular diseases.


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 }}

PinLan Li其他文献

PinLan Li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('PinLan Li', 18)}}的其他基金

Lysosome dysfunction in podocytopathy and associated hypertension
足细胞病和相关高血压中的溶酶体功能障碍
  • 批准号:
    9792379
  • 财政年份:
    2018
  • 资助金额:
    $ 40.02万
  • 项目类别:
Lysosome dysfunction in podocytopathy and associated hypertension
足细胞病和相关高血压中的溶酶体功能障碍
  • 批准号:
    10461007
  • 财政年份:
    2018
  • 资助金额:
    $ 40.02万
  • 项目类别:
Lysosome dysfunction in podocytopathy and associated hypertension
足细胞病和相关高血压中的溶酶体功能障碍
  • 批准号:
    10218151
  • 财政年份:
    2018
  • 资助金额:
    $ 40.02万
  • 项目类别:
Lysosome Trafficking Dysregulation of Arterial Myocytes in Atherogenesis
动脉粥样硬化中动脉肌细胞的溶酶体运输失调
  • 批准号:
    9097883
  • 财政年份:
    2015
  • 资助金额:
    $ 40.02万
  • 项目类别:
Renomedullary metabolism of anandamide and blood pressure regulation
anandamide 的肾髓代谢与血压调节
  • 批准号:
    9054518
  • 财政年份:
    2015
  • 资助金额:
    $ 40.02万
  • 项目类别:
Lysosome Trafficking Dysregulation of Arterial Myocytes in Atherogenesis
动脉粥样硬化中动脉肌细胞的溶酶体运输失调
  • 批准号:
    9201339
  • 财政年份:
    2015
  • 资助金额:
    $ 40.02万
  • 项目类别:
Lysosome Trafficking Dysregulation of Arterial Myocytes in Atherogenesis
动脉粥样硬化中动脉肌细胞的溶酶体运输失调
  • 批准号:
    9002899
  • 财政年份:
    2015
  • 资助金额:
    $ 40.02万
  • 项目类别:
Epigenetic Regulation of Lysosomal Ceramide Signaling and Function in Arterial Myocytes: Role of Kmt6 Gene
动脉肌细胞溶酶体神经酰胺信号和功能的表观遗传调控:Kmt6 基因的作用
  • 批准号:
    10450193
  • 财政年份:
    2014
  • 资助金额:
    $ 40.02万
  • 项目类别:
Renomedullary metabolism of anandamide and blood pressure regulation
anandamide 的肾髓代谢与血压调节
  • 批准号:
    8852753
  • 财政年份:
    2014
  • 资助金额:
    $ 40.02万
  • 项目类别:
Lysosome Trafficking Dysregulation of Arterial Myocytes in Atherogenesis
动脉粥样硬化中动脉肌细胞的溶酶体运输失调
  • 批准号:
    8842197
  • 财政年份:
    2014
  • 资助金额:
    $ 40.02万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 40.02万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了