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Sphingolipid signaling in age-associated vascular pathology

Sphingolipid signaling in age-associated vascular pathology
年龄相关血管病理学中的鞘脂信号传导
批准号:
10506516
负责人:
Timothy Tun Hla
金额:
$50.55万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-01 至 2027-05-31

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中文摘要
翻译
摘要 与年龄相关的血管功能下降是器官功能下降的关键因素, 活力、抗压能力和增加的发病率/死亡率。我们实验室做了 关于脂质介质(鞘脂和前列腺素)如何增强的长期贡献 血管内皮细胞(EC)的功能和对病理过程的恢复能力。我们最近的 数据表明,EC 保护性鞘氨醇 1-磷酸 (S1P) 随年龄的增长而下降 信号传导导致 EC 功能障碍和各种器官的病理学。具体来说,循环 通过 EC S1P 受体 1 (S1PR1) 的 HDL 结合 S1P 信号传导是增强 EC 的恢复能力以及旨在对抗其年龄依赖性衰退的治疗策略 有效减少器官病理。这一前提得到了公正研究的进一步支持 在人类中,ApoM(HDL 上的 S1P 伴侣)表现出年龄依赖性下降。我们 假设衰老会损害血管保护性 S1P 通路,从而增强 EC 弹性,从而导致器官功能迅速下降。该假设的推论是 基于机制的 EC S1PR1 通路治疗增强将降低发生率 器官特异性 EC 的下降。为了了解器官特异性血管老化机制,我们 从新鲜分离的 EC 中分析了全球转录组和染色质调控位点 正常小鼠主动脉、肺和视网膜。这些器官的 EC 缺陷会导致动脉粥样硬化, 降低中枢神经系统(CNS)对病毒感染和血管病理的抵抗力, 分别。首先,我们将表征衰老诱导的主动脉内皮细胞 2 (AEC2) S1PR1 信号减弱同时表现出炎症和纤维化基因的人群 签名。我们将定义 AEC2 细胞的年龄相关染色质调节因子并评估 S1PR1/Gi 偏向信号抵消老年人这种病理性 EC 表型变化的能力 老鼠。其次,我们将测试肺 EC (LEC) 中 EC S1PR1 信号传导支持的假设 抵抗病毒感染的能力。衰老减弱 LEC S1PR1 信号传导的机制 将被阐明。模仿 HDL-S1P 抑制病理性的治疗策略 将测试表型。三、使用视网膜EC(REC)作为CNS模型 脉管系统,我们将检查 S1PR1 信号是否可以对抗与年龄相关的屏障破坏, 转运蛋白基因表达和星形胶质细胞增生,单独或与 Wnt 组合 信号激活剂。这些研究预计将带来新的见解,通过脂质 介质在衰老过程中会导致血管功能障碍和疾病,最终可能 导致对抗与年龄相关的器官功能障碍和衰退的新治疗策略。
英文摘要
SUMMARY Age-related decline in vascular function is a key factor in decreased organ function, vitality, resistance to stress and increased morbidity/ mortality. Our laboratory has made long-standing contributions about how lipid mediators (sphingolipids and prostanoids) enhance vascular endothelial cells (EC) function and resilience to pathological processes. Our recent data suggest that age-dependent decline in EC protective sphingosine 1-phosphate (S1P) signaling contributes to EC dysfunction and pathology of various organs. Specifically, circulatory HDL-bound S1P signaling via EC S1P receptor-1 (S1PR1) is a key mechanism that enhances EC resilience and that therapeutic strategies designed to counter its age-dependent decline was efficacious in reducing organ pathology. This premise is further supported by unbiased studies in humans which show age-dependent decrease in ApoM, the S1P chaperone on HDL. We hypothesize that aging compromises vasculoprotective S1P pathway which enhances EC resilience, thus contributing to rapid decline in organ function. The corollary of the hypothesis is that mechanism-based therapeutic enhancement of EC S1PR1 pathway will decrease the rate of decline of organ-specific EC. To understand organ-specific vascular aging mechanisms, we profiled the transcriptome and chromatin regulatory sites globally from freshly isolated EC from normal mouse aorta, lung and retina. EC defects in these organs lead to atherosclerosis, reduced resistance to viral infections and vascular pathology in central nervous system (CNS), respectively. First, we will characterize an aging-induced aortic endothelial cell-2 (AEC2) population which has attenuated S1PR1 signal while exhibiting inflammatory and fibrotic gene signature. We will define age-associated chromatin regulators of AEC2 cells and assess the ability of S1PR1/ Gi-biased signals to counteract this pathological EC phenotype change in aged mice. Second, we will test the hypothesis that EC S1PR1 signaling in lung EC (LEC) supports resilience against viral infections. Mechanisms by which aging attenuates LEC S1PR1 signaling will be elucidated. Therapeutic strategies that mimic HDL-S1P that suppress pathological phenotypes will be tested. Third, using the retinal EC (REC) as a model of the CNS vasculature, we will examine whether S1PR1 signal can counter age-related barrier breach, transporter gene expression and astrogliosis either alone or in combination with the Wnt signaling activators. These studies are anticipated to lead to new insights by which lipid mediators contribute to vascular dysfunction and disease during aging, which could ultimately lead to novel therapeutic strategies to combat age-related organ dysfunction and decline.
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会议论文
Myeloid sphingolipid regulation of tissue resolution and regeneration responses
  • 批准号:
    10562518
  • 项目类别:
  • 资助金额:
    $57.66万
  • 财政年份:
    2022
  • 负责人:
    Timothy Tun Hla
  • 依托单位:
Myeloid sphingolipid regulation of tissue resolution and regeneration responses
  • 批准号:
    10708956
  • 项目类别:
  • 资助金额:
    $58.97万
  • 财政年份:
    2022
  • 负责人:
    Timothy Tun Hla
  • 依托单位:
G protein-coupled receptor regulation of transcriptional mechanisms in the retinal vasculature.
  • 批准号:
    10596099
  • 项目类别:
  • 资助金额:
    $47.53万
  • 财政年份:
    2021
  • 负责人:
    Timothy Tun Hla
  • 依托单位:
G protein-coupled receptor regulation of transcriptional mechanisms in the retinal vasculature.
  • 批准号:
    10390409
  • 项目类别:
  • 资助金额:
    $46.11万
  • 财政年份:
    2021
  • 负责人:
    Timothy Tun Hla
  • 依托单位:
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