Sphingosine-1-phosphate induced modulation of inflammation in aging and Alzheimer's disease

1-磷酸鞘氨醇诱导衰老和阿尔茨海默病炎症的调节

基本信息

  • 批准号:
    9403429
  • 负责人:
  • 金额:
    $ 283.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

Sphingosine 1-phosphate (S1P) is a bioactive molecule that signals by activating S1P receptors (S1P1-5) to regulate cellular processes in systemic immunity and inflammation. Accumulating evidence indicates that ab- normalities of S1P signaling are associated with brain aging and with the pathophysiology of Alzheimer's dis- ease (AD). Fingolimod, a sphingosine analog used for the treatment of multiple sclerosis (MS), acts through S1P1 in lymphocytes to reduce their infiltration into the CNS and thereby provides therapeutic effects against subsequent neuroinflammation. Fingolimod crosses the blood brain barrier and emerging evidence suggests the direct neuroprotective effect of fingolimod on CNS cells. In experimental models of AD fingolimod appears to reduce the production and the neurotoxicity of Aβ peptide and promote neuroprotection of microglia and neurons. We have reported that in 5xFAD mice, a transgenic model of AD, oral fingolimod treatment decreases the activation of microglia and reactive astrocytes, decreases Aβ levels, and increases hippocampal neuro- genesis. Our preliminary data show that most of the neuroprotective effects of fingolimod in 5xFAD mice occur at a low dose with major effects on neuroinflammatory markers. We hypothesize that aging alters the S1P sig- naling system in the brain and drives the proinflammatory activation of astrocytes and microglia that is acceler- ated by the buildup of Aβ and that treatment with S1P modulators will interfere with this process and may affect age- and AD-related neuropathology and behavioral deficits. To test this hypothesis we will use two different transgenic mouse models of AD (5xFAD and PSAPP) that accumulate Aβ at different rates such that similar amounts of Aβ are deposited in the brain at different ages. The study includes 3 aims. The first two aims are mechanistic studies to determine the effect of age and AD-like pathology on the S1P system in wild type mice and in the mouse models of AD (aim 1) and to determine the effects of S1P receptor modulators on neuroin- flammation in aging and AD mouse models and on AD-related neuropathology and cognitive function in these models (aim 2). The latter studies will include a prevention arm by treating the mice before the emergence of AD-like pathology until old age (1-18 months), and an advanced disease arm by treating the mice with well- established pathology (15-18 months). The outcome measures will include cognitive behavior, amyloidosis, ac- tivation of astrocytes and microglia, S1P system, neurotrophin signaling, e.g. BDNF/TrkB, cytokines, synaptic- glial- and apoptotic markers, and small molecules determined by magnetic resonance spectroscopy (MRS) that reflect neural metabolism, excitotoxic, oxidative, and osmotic stress, as well as membrane integrity. Machine learning tools will be employed to integrate these data sets. The third aim will be the translational arm of the study to determine the effects of S1P modulation on indices of neuronal and glial function in aging and in AD mouse models using noninvasive techniques including in vivo magnetic resonance spectroscopy imaging and spectroscopy (MRI/MRS) and positron emission tomography.
1-磷酸鞘氨醇(S1P)是一种生物活性分子,通过激活S1P受体(S1P1-5)来传递信号 调节全身免疫和炎症中的细胞过程。越来越多的证据表明,ab- S1P信号的异常与脑老化和阿尔茨海默病的病理生理相关 缓动(AD)。Fingolimod是一种用于治疗多发性硬化症(MS)的鞘氨醇类似物,通过 S1P1,以减少其对中枢神经系统的渗透,从而提供治疗疟疾的效果 随后的神经炎。Fingolimod跨越血脑屏障,新出现的证据表明 Fingolimod对中枢神经系统细胞的直接神经保护作用在AD的实验模型中出现了Fingolimod 减少β多肽的产生和神经毒性,促进小胶质细胞和 神经元。我们已经报道,在5xFAD小鼠中,AD的转基因模型,口服Fingolimod治疗减少 激活小胶质细胞和反应性星形胶质细胞,降低Aβ水平,增加海马神经细胞数量。 创世纪。我们的初步数据显示,在5xFAD小鼠中,Fingolimod的大部分神经保护作用发生在 低剂量,对神经炎性标志物有显著影响。我们假设老化会改变S1P信号- 大脑中的NALL系统,并驱动星形胶质细胞和小胶质细胞的促炎性激活,这是加速- 由于Aβ的积聚和使用S1P调制器的治疗将干扰这一过程并可能影响 年龄和阿尔茨海默病相关的神经病理和行为缺陷。为了检验这一假设,我们将使用两种不同的 以不同速率积累Aβ的AD转基因小鼠模型(5xFAD和PSAPP) 不同年龄的人大脑中会有大量的Aβ沉积。本研究包括三个目标。头两个目标是 AGE和AD样病理对野生型小鼠S1P系统影响的机制研究 以及在AD小鼠模型(AIM 1)中的作用,并确定S1P受体调节剂对神经肽的影响。 衰老和AD小鼠模型中的炎性反应及其对AD相关神经病理和认知功能的影响 模型(目标2)。后一项研究将包括通过在老鼠出现之前对其进行治疗来预防 AD样病理直到老年(1-18个月),晚期疾病臂通过很好地治疗小鼠- 病理确诊(15-18个月)。结果测量将包括认知行为、淀粉样变性、AC- 星形胶质细胞和小胶质细胞的激活,S1P系统,神经营养因子信号,如BDNF/TrkB,细胞因子,突触- 胶质细胞和凋亡标志物,以及由磁共振波谱(MRS)确定的小分子 反映神经代谢、兴奋毒性、氧化和渗透应激,以及膜的完整性。机器 将使用学习工具来整合这些数据集。第三个目标将是 S1P调节对衰老和阿尔茨海默病神经元和神经胶质功能指标影响的研究 使用非侵入性技术的小鼠模型,包括体内磁共振成像和 光谱学(MRI/MRS)和正电子发射断层扫描。

项目成果

期刊论文数量(3)
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 }}

ALPASLAN DEDEOGLU其他文献

ALPASLAN DEDEOGLU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('ALPASLAN DEDEOGLU', 18)}}的其他基金

Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis
1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点
  • 批准号:
    10011983
  • 财政年份:
    2021
  • 资助金额:
    $ 283.08万
  • 项目类别:
Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis
1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点
  • 批准号:
    10476986
  • 财政年份:
    2021
  • 资助金额:
    $ 283.08万
  • 项目类别:
Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis
1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点
  • 批准号:
    10664897
  • 财政年份:
    2021
  • 资助金额:
    $ 283.08万
  • 项目类别:
Targeting the sphingosine-1-phosphate system in a mouse model of Gulf War Veterans' Illness
针对海湾战争退伍军人疾病小鼠模型中的 1-磷酸鞘氨醇系统
  • 批准号:
    10293531
  • 财政年份:
    2020
  • 资助金额:
    $ 283.08万
  • 项目类别:
Protective roles of taurine in Alzheimer's disease brain
牛磺酸对阿尔茨海默病大脑的保护作用
  • 批准号:
    10055586
  • 财政年份:
    2020
  • 资助金额:
    $ 283.08万
  • 项目类别:
Targeting the sphingosine-1-phosphate system in a mouse model of Gulf War Veterans' Illness
针对海湾战争退伍军人疾病小鼠模型中的 1-磷酸鞘氨醇系统
  • 批准号:
    9891211
  • 财政年份:
    2020
  • 资助金额:
    $ 283.08万
  • 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
  • 批准号:
    8815008
  • 财政年份:
    2014
  • 资助金额:
    $ 283.08万
  • 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
  • 批准号:
    8974377
  • 财政年份:
    2014
  • 资助金额:
    $ 283.08万
  • 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
  • 批准号:
    8660378
  • 财政年份:
    2014
  • 资助金额:
    $ 283.08万
  • 项目类别:
Novel neurotrophic therapies in an optimized mouse model of GWVI
优化的 GWVI 小鼠模型中的新型神经营养疗法
  • 批准号:
    9339554
  • 财政年份:
    2014
  • 资助金额:
    $ 283.08万
  • 项目类别:

相似国自然基金

靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    0 万元
  • 项目类别:
    面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
  • 批准号:
    2023JJ50274
  • 批准年份:
    2023
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 批准年份:
    2019
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
  • 批准号:
    81602908
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
  • 批准号:
    81501928
  • 批准年份:
    2015
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

The Phenomenon of Stem Cell Aging according to Methylation Estimates of Age After Hematopoietic Stem Cell Transplantation
根据造血干细胞移植后甲基化年龄估算干细胞衰老现象
  • 批准号:
    23K07844
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Analysis of Age-dependent Functional Changes in Skeletal Muscle CB1 Receptors by an in Vitro Model of Aging-related Muscle Atrophy
通过衰老相关性肌肉萎缩的体外模型分析骨骼肌 CB1 受体的年龄依赖性功能变化
  • 批准号:
    22KJ2960
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Joint U.S.-Japan Measures for Aging and Dementia Derived from the Prevention of Age-Related and Noise-induced Hearing Loss
美日针对预防与年龄相关和噪声引起的听力损失而导致的老龄化和痴呆症联合措施
  • 批准号:
    23KK0156
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
    Fund for the Promotion of Joint International Research (International Collaborative Research)
The Effects of Muscle Fatigability on Gait Instability in Aging and Age-Related Falls Risk
肌肉疲劳对衰老步态不稳定性和年龄相关跌倒风险的影响
  • 批准号:
    10677409
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
Characterizing gut physiology by age, frailty, and sex: assessing the role of the aging gut in "inflamm-aging"
按年龄、虚弱和性别表征肠道生理学特征:评估衰老肠道在“炎症衰老”中的作用
  • 批准号:
    497927
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
Role of AGE/RAGEsignaling as a driver of pathological aging in the brain
AGE/RAGE信号传导作为大脑病理性衰老驱动因素的作用
  • 批准号:
    10836835
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
Deciphering the role of osteopontin in the aging eye and age-related macular degeneration
破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用
  • 批准号:
    10679287
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
Elucidation of the protein kinase NLK-mediated aging mechanisms and treatment of age-related diseases
阐明蛋白激酶NLK介导的衰老机制及年龄相关疾病的治疗
  • 批准号:
    23K06378
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Underlying mechanisms of age-related changes in ingestive behaviors: From the perspective of the aging brain and deterioration of the gustatory system.
与年龄相关的摄入行为变化的潜在机制:从大脑老化和味觉系统退化的角度来看。
  • 批准号:
    23K10845
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Targeting Age-Activated Proinflammatory Chemokine Signaling by CCL2/11 to Enhance Skeletal Muscle Regeneration in Aging
通过 CCL2/11 靶向年龄激活的促炎趋化因子信号传导以增强衰老过程中的骨骼肌再生
  • 批准号:
    478877
  • 财政年份:
    2023
  • 资助金额:
    $ 283.08万
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了