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: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506516
• 关键词: Address; Age; Aging; Air; Alveolar; Aorta; Architecture; Atherosclerosis; Attenuated; Blindness; Blood Vessels; Cell Line; Cell physiology; Cells; Chromatin; Chronic; Clinical; Data; Defect; Dementia; Disease; Endothelial Cells; Event; Exhibits; Frequencies; Functional disorder; Gases; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Genetic Transcription; High Density Lipoproteins; Host Defense; Human; Inflammation; Inflammatory; Injury; Knock-in; Knowledge; Laboratories; Lead; Lung; Modeling; Molecular Chaperones; Morbidity - disease rate; Mosaicism; Mus; Nerve Degeneration; Neuraxis; Organ; Outcome; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Pattern; Phenotype; Physiological; Population; Prostaglandins; Pulmonary Fibrosis; Resistance; Retina; SLC2A1 gene; Signal Pathway; Signal Transduction; Site; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stress; Supporting Cell; TFRC gene; Testing; Therapeutic; Thrombosis; Transgenic Organisms; Vascular Diseases; Vascular Endothelial Cell; Vascular System; Vesicle; Viral; Virus Diseases; WNT Signaling Pathway; age related; aged; aging population; astrogliosis; base; beta-arrestin; combat; design; frailty; genetic signature; human old age (65+); influenza infection; insight; lipid mediator; mortality; mouse genetics; mouse model; mutant; novel therapeutic intervention; programs; pulmonary function; resilience; senescence; single-cell RNA sequencing; sphingosine 1-phosphate; transcriptome; vascular abnormality

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.

总结 与血管功能相关的血管功能下降是器官功能下降的关键因素， 生命力、抗压能力和发病率/死亡率增加。我们的实验室 关于脂质介质（鞘脂和前列腺素类）如何增强 血管内皮细胞（EC）的功能和对病理过程的恢复力。我们最近 数据表明，EC保护性鞘氨醇1-磷酸（S1 P）的年龄依赖性下降， 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 S1 P受体-1（S1 PR 1）的HDL结合的S1 P信号传导是增强 EC弹性和旨在对抗其年龄依赖性下降的治疗策略， 有效减少器官病理。这一前提得到了无偏见研究的进一步支持 显示ApoM（HDL上的S1 P伴侣）的年龄依赖性降低。我们 假设衰老损害了血管保护性S1 P通路， 恢复力，从而导致器官功能迅速下降。这个假设的推论是 基于机制的EC S1 PR 1通路的治疗增强将降低 器官特异性EC下降。为了了解器官特异性血管衰老机制，我们 分析了来自新鲜分离的EC的转录组和染色质调控位点， 正常小鼠主动脉、肺和视网膜。这些器官中的EC缺陷导致动脉粥样硬化， 降低对中枢神经系统（CNS）中病毒感染和血管病变的抗性， 分别首先，我们将描述衰老诱导的主动脉内皮细胞-2（AEC 2） 具有减弱的S1 PR 1信号同时显示炎性和纤维化基因的群体 签名.我们将定义AEC 2细胞的年龄相关染色质调节因子，并评估其对细胞增殖的影响。 S1 PR 1/ Gi-biased信号抵消老年人这种病理性EC表型变化的能力 小鼠其次，我们将检验肺EC（LEC）中EC S1 PR 1信号传导支持 抵御病毒感染的能力。衰老减弱LEC S1 PR 1信号传导的机制 将被阐明。模拟HDL-S1 P的治疗策略， 将测试表型。第三，使用视网膜EC（REC）作为CNS的模型， 血管，我们将研究S1 PR 1信号是否可以对抗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 信号激活剂。这些研究预计将导致新的见解， 介质有助于血管功能障碍和疾病在衰老过程中，这可能最终 从而导致对抗与年龄相关器官功能障碍和衰退的新的治疗策略。