The impact of sphingosine-1-phosphate (S1P)-lyase deficiency on astrocyte physiology and on epigenetic regulation
1-磷酸鞘氨醇 (S1P) 裂解酶缺陷对星形胶质细胞生理学和表观遗传调控的影响
基本信息
- 批准号:434626472
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2020
- 资助国家:德国
- 起止时间:2019-12-31 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Sphingosine-1-phosphate (S1P), an evolutionarily conserved catabolic intermediate of sphingolipid metabolism regulates diverse biological processes in the brain including neural development, differentiation, and survival. Another interesting finding is its function in the regulation of histone acetylation. S1P specifically binds to histone deacetylases HDAC1 and HDAC2 thus inhibiting their enzymatic activity and preventing the removal of acetyl groups from lysine residues within histone tails. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism generating ethanolamine phosphate and a long-chain aldehyde. There is no doubt on the essential role of S1P in brain development. Yet, reports on the involvement of S1P in the pathology of neurodegenerative diseases are rather conflicting. In an attempt to clarify the function of S1P in the brain, we generated a mouse model in which SGPL1 was inactivated specifically in neural cells (SGPL1fl/fl/Nes). As expected, SGPL1 ablation leads to S1P accumulation in the brain causing neuronal ER-stress, an increase in intracellular calcium, impairment of presynaptic architecture and function, accompanied by cognitive deficits in mice. In addition, we demonstrated that SGPL1 deficiency blocks neuronal autophagy at its early stages because of reduced phosphatidylethanolamine (PE) production. Thus accumulation of S1P and the simultaneous decline of PE in SGPL1 deficient brains cause considerable neuronal damage. As neuronal damage might induce inflammation, we investigated the microglial alterations as a result of S1P accumulation in neural cells. We evidenced increased microglial activation in the brains of SGPL1fl/fl/Nes mice as shown by morphological as well as biochemical markers. Also, an increased secretion of pro-inflammatory cytokines in FACS-sorted and cultured microglia from SGPL1fl/fl/Nes mice was noticed. Given the increasing number of human neuropathalogies as a result of mutations in the gene encoding SGPL1, we decided to extend our studies and analyse on the one hand the fate of astrocytes in SGPL1fl/fl/Nes mice and on the other hand the epigenetic consequences of S1P accumulation in SGPL1 depleted brains. The present project thus aims to answer two central questions:I) How does neural-targeted ablation of SGPL1 induce astrogliosis?II) Which molecular mechanism underlies S1P dependent regulation of histone acetylation?Specific goals are:Ia. To explore the causes of astrogliosis and of its consequences. Ib. To assess autophagy in primary cultured astrocytes.Ic. To verify our hypothesis regarding the molecular mechanism that links SGPL1 activity, activation of astrocytes and autophagy.IIa. To investigate histone acetylation in SGPL1 deficient brains.IIb: To study the involvement of calcium regarding histone acetylation.Preliminary results strongly encourage implementation of this project.
鞘氨醇-1-磷酸(S1P)是一种进化上保守的鞘磷脂代谢的分解代谢中间体,调节着大脑中包括神经发育、分化和生存在内的多种生物学过程。另一个有趣的发现是它在组蛋白乙酰化调节中的作用。S1P与组蛋白脱乙酰基酶HDAC1和HDAC2特异性结合,从而抑制它们的酶活性,并阻止组蛋白尾部赖氨酸残基中乙酰基的去除。S1P裂解酶(SGPL1)在鞘磷脂分解代谢的最后一步不可逆地裂解S1P,生成乙醇胺磷酸和长链醛。毫无疑问,S1P在大脑发育中起着至关重要的作用。然而,关于S1P参与神经退行性疾病的病理的报道是相当矛盾的。为了阐明S1P在大脑中的功能,我们建立了一个小鼠模型,在该模型中,SGPL1在神经细胞(SGPL1fl/fl/nes)中被特异性失活。正如预期的那样,SGPL1消融导致S1P在脑内积聚,导致神经元内质网应激,细胞内钙离子增加,突触前结构和功能受损,并伴有认知障碍。此外,我们还证明了SGPL1缺乏会在早期阶段阻止神经元的自噬,因为磷脂酰乙醇胺(PE)的产生减少了。因此,在SGPL1缺乏的脑中,S1P的积聚和PE的同时下降会导致相当大的神经元损伤。由于神经元损伤可能导致炎症,我们研究了S1P在神经细胞内积聚导致的小胶质细胞变化。我们证实了SGPL1fl/fl/nes小鼠脑内小胶质细胞的激活,这是形态和生化标记所显示的。此外,从SGPL1fl/fl/nes小鼠分离和培养的小胶质细胞中,促炎症细胞因子的分泌也增加。鉴于编码SGPL1的基因突变导致人类神经病理疾病的数量增加,我们决定扩大我们的研究,一方面分析SGPL1fl/fl/nes小鼠星形胶质细胞的命运,另一方面分析SGPL1枯竭脑中S1P积聚的表观遗传学后果。因此,本项目旨在回答两个核心问题:i)神经靶向消融SGPL1是如何诱导星形胶质细胞增生的?ii)S1P依赖的调节组蛋白乙酰化的分子机制是什么?具体目标是:IA。探讨星形胶质细胞增生症的病因及其后果。IB。评估原代培养星形胶质细胞的自噬作用。为了验证我们关于SGPL1活性、星形胶质细胞激活和自噬的分子机制的假设。目的:研究组蛋白乙酰化在SGPL1缺陷脑中的作用。IIb:研究钙与组蛋白乙酰化的关系。初步结果强烈支持该项目的实施。
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 }}
Privatdozentin Dr. Gerhild van Echten-Deckert, Ph.D.其他文献
Privatdozentin Dr. Gerhild van Echten-Deckert, Ph.D.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('Privatdozentin Dr. Gerhild van Echten-Deckert, Ph.D.', 18)}}的其他基金
Sphingosine-1-phosphate and Alzheimer's disease
1-磷酸鞘氨醇和阿尔茨海默病
- 批准号:
172556834 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Priority Programmes
Pathophysiologische Bedeutung der Gallensäure beta-Glukosidase (GBA2): Untersuchungen an GBA2-defizienten Mäusen, Mutationsanalysen von M. Gaucher Patienten am GBA2-Gen
胆汁酸 β-葡萄糖苷酶 (GBA2) 的病理生理学意义:对 GBA2 缺陷小鼠的研究,M. Gaucher 患者 GBA2 基因的突变分析
- 批准号:
53797617 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Research Grants
Cell growth regulation by sphingosine-1-phosphate and ceramide
1-磷酸鞘氨醇和神经酰胺调节细胞生长
- 批准号:
5401549 - 财政年份:2003
- 资助金额:
-- - 项目类别:
Research Grants
Funktion von Sphingolipiden nach operativem Darmtrauma
外科肠道创伤后鞘脂的功能
- 批准号:
5399572 - 财政年份:2003
- 资助金额:
-- - 项目类别:
Clinical Research Units
相似国自然基金
Sphingosine通路在肺癌发生的作用机制
- 批准号:82172565
- 批准年份:2021
- 资助金额:55 万元
- 项目类别:面上项目
鞘氨醇衍生物靶向Cer-Sph-S1P调控乳腺癌他莫昔芬耐药及免疫抑制
- 批准号:
- 批准年份:2019
- 资助金额:10.0 万元
- 项目类别:省市级项目
磷脂转运蛋白通过磷酸鞘氨醇1影响高密度脂蛋白抗动脉粥样硬化功能的分子机制
- 批准号:81070247
- 批准年份:2010
- 资助金额:33.0 万元
- 项目类别:面上项目
S1P介导骨髓间充质干细胞参与肝纤维化的机制研究
- 批准号:30971348
- 批准年份:2009
- 资助金额:31.0 万元
- 项目类别:面上项目
相似海外基金
The impact of ER stress on Salmonella Typhimurium infections
内质网应激对鼠伤寒沙门氏菌感染的影响
- 批准号:
10708073 - 财政年份:2022
- 资助金额:
-- - 项目类别:
The impact of ER stress on Salmonella Typhimurium infections
内质网应激对鼠伤寒沙门氏菌感染的影响
- 批准号:
10565316 - 财政年份:2022
- 资助金额:
-- - 项目类别:
The molecular and spatial interactions between antibody suppressor CD8+ T cells and B cells that regulate alloantibody production after transplant
抗体抑制 CD8 T 细胞和 B 细胞之间的分子和空间相互作用调节移植后同种抗体的产生
- 批准号:
10431812 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Regulation of host immunity to impact virus persistence
调节宿主免疫力以影响病毒的持久性
- 批准号:
10293370 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Regulation of host immunity to impact virus persistence
调节宿主免疫力以影响病毒的持久性
- 批准号:
10424601 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Regulation of host immunity to impact virus persistence
调节宿主免疫力以影响病毒的持久性
- 批准号:
10640180 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Sphingolipids and their Impact in Corneal Wound Healing
鞘脂及其对角膜伤口愈合的影响
- 批准号:
10405111 - 财政年份:2020
- 资助金额:
-- - 项目类别:














{{item.name}}会员




