Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice

RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果

基本信息

  • 批准号:
    10609791
  • 负责人:
  • 金额:
    --
  • 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
  • 起止时间:
    2022-01-01 至 2025-12-31
  • 项目状态:
    未结题

项目摘要

Ischemic stroke is a leading cause of death and long-term disability in elderly veterans. It is well established that post-stroke immune responses have a substantial impact on the progression of ischemic brain injury and brain recovery, but there are no clinical treatments that successfully harness the restorative power of the immune system while also tempering inflammation-induced secondary injuries. The reasons for this gap are multifactorial, but include a preclinical overemphasis on young adult animals, which simply do not display the same pathophysiological mechanisms underlying brain ischemia as the aged, including the dynamic inflammatory dialogue between glia and neurons. We propose to fill the critical gap in elderly veteran care by focusing on aged animals and repurposing an FDA-approved drug at low doses to correct hyperactive immune responses and tip the balance in favor of sustained tissue healing and long-term recovery of neurological functions. To commence this goal, we have conducted pilot studies on proteins that are highly enriched in microglia and brain-infiltrating macrophages (Mi/MΦ)—including the retinoid X receptor (RXR). RXR binds to peroxisome proliferator-activated receptor γ (PPARγ) to govern the transcription of genes critically involved in redox status, inflammation resolution, trophic factor production, and metabolism. Thus, RXR/PPARγ activation lies at the apex of a decision tree for arbitrating between polymorphic, often-opposing immune responses in Mi and MΦ. To engage this important biological target, we have chosen a selective RXR agonist, bexarotene, an FDA-approved antineoplastic agent lacking in pan-immunosuppressive effects and with excellent safety profiles. The scientific premise underlying the engagement of the RXR/PPARγ axis as a superior biological target for stroke is its ability to titrate immune balance toward anti-inflammatory/pro-repair phenotypes, while avoiding indiscriminate suppression of immune function in the vulnerable elderly. The premise of this proposal is also strengthened by our new preliminary discoveries: 1) Mi/MΦ-specific conditional knockout (mKO) of RXR or PPARγ worsens long-term outcomes after permanent distal middle cerebral artery occlusion (dMCAO) in mice. 2) RXR or PPARγ mKO mice exhibit impairments in post-stroke efferocytosis (Mi/MΦ phagocytosis of dying neurons) and resolution of neuroinflammation. 3) PPARγ mKO alters the Mi/MΦ transcriptome, with heightened proinflammatory responses and impaired phagocytosis according to RNA sequencing data. 4) Excitingly, intraperitoneal administration of low-dose bexarotene (10-20 times lower than in clinical trials) improves long-term outcomes after dMCAO in aged mice (20 months old). Accordingly, our research group is now in an excellent position to test the following core hypothesis: Activation of RXR improves long-term outcomes after ischemic stroke by promoting efferocytosis and inflammation-resolving, pro- repair microglial/macrophage responses. If funded, we will tackle three aims in a timely and efficient manner: Aim 1: Systematically test if bexarotene improves long-term histological and functional outcomes in aged (20 months old) stroke mice of both sexes. Aim 2: Test the subhypothesis that bexarotene promotes efferocytosis in Mi/MΦ and attenuates acute ischemic brain injury via activation of RXR. Aim 3: Test the subhypothesis that enhanced inflammation-resolving, pro-repair actions of Mi/MΦ contribute to bexarotene-afforded, RXR-dependent long-term beneficial effects against stroke. We will use aged subjects of both sexes and deploy state-of-the-art tools, such as cell-specific, conditional RXR knockout, electrophysiological measurements, stereological counting, and a battery of established behavior tests to gain novel mechanistic insights into the role of Mi/MΦ in stroke evolution. A rigorously confirmed beneficial effect of bexarotene on aged mice would facilitate its clinical translation into a potential stroke therapy for military men and women as well as elderly civilians.
缺血性中风是老退伍军人的死亡和长期残疾的主要原因。已经确定了 冲程后免疫调查会对缺血性脑损伤和脑的进展产生重大影响 恢复,但没有成功利用免疫的恢复能力的临床治疗 系统同时还原感染引起的继发损伤。此差距的原因是多因素, 但包括对年​​轻动物的过分强调,这些动物根本不显示相同 脑缺血的病理生理机制是年龄的,包括动态炎症 神经胶质和神经元之间的对话。我们建议通过专注于老年人来填补老兵护理的关键空白 动物并以低剂量重新利用FDA批准的药物,以纠正过度活跃的免疫回报和尖端 平衡有利于持续的组织愈合和神经功能的长期恢复。 为了开始这个目标,我们已经对高度富含小胶质细胞的蛋白质进行了试点研究 和脑浸润巨噬细胞(MI/Mφ) - 包括性类维生素X受体(RXR)。 RXR结合过氧组 增生剂激活的受体γ(PPARγ)控制着与氧化还原状态有关的基因的转录, 炎症分辨率,营养因子的产生和代谢。那就是RXR/PPARγ激活位于顶点 在MI和Mφ中通常会在多态性的,经常呼吸的免疫反应之间进行仲裁的决策树。到 参与这个重要的生物学靶标,我们选择了选择性RXR激动剂Bexarotene,一个FDA批准 缺乏泛免疫抑制作用和出色的安全性概况的抗塑料剂。科学 RXR/PPARγ轴作为中风的超级生物学目标的前提是其能力 滴定免疫平衡朝着抗炎/促进式表型,同时避免不加区别 较早的弱势群体抑制免疫功能。 我们的新初步发现也加强了该提案的前提:1)MI/Mφ特异性 RXR或PPARγ的有条件敲除(MKO)在永久远端中间后的长期结局恶化 小鼠的脑动脉阻塞(DMCAO)。 2)RXR或PPARγMKO小鼠展示后冲程障碍 肿瘤(MI/Mφ吞噬作用的垂死神经元)和神经炎症的分辨率。 3)PPARγMKO改变 MI/Mφ转录组,促炎反应增强,吞噬作用受损 RNA测序数据。 4)令人兴奋的是,腹膜内给予低剂量贝克索烯(低10-20倍 在临床试验中,比临床试验更适合DMCAO后的长期结局(20个月大)。根据我们的说法 研究小组现在处于测试以下核心假设的绝佳位置:RXR的激活改善 缺血性中风后的长期结局,通过促进肿瘤和注射疗法,促成 修复小胶质细胞/巨噬细胞反应。如果资助,我们将及时有效地解决三个目标: AIM 1:系统地测试Bexarotene是否改善了老年人的长期组织学和功能结果 (20个月大)两性的中风小鼠。 AIM 2:测试贝克索烯可促进MI/Mφ的肿瘤病并减弱急性的亚类假设 通过激活RXR的缺血性脑损伤。 AIM 3:测试以MI/Mφ的增强解析,促进的动作的亚物种 为了呈现贝克索烯,RXR依赖性的长期有益作用针对中风。 我们将使用男女的老年对象和部署最先进的工具,例如细胞特定的条件 RXR敲除,电生理测量,立体计数和一系列既定行为 测试以获得对MI/Mφ在中风演化中的作用的新机械见解。严格确认 北沙烯对老年小鼠的有益作用将促进其临床转化为潜在的中风疗法 对于军事男女,以及古老的平民。

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)

暂无数据

数据更新时间:2024-06-01

Jun Chen其他文献

Corrosion wear characteristics of TC4, 316 stainless steel, and Monel K500 in artificial seawater
TC4、316不锈钢、蒙乃尔K500在人工海水中的腐蚀磨损特性
  • DOI:
    10.1039/c7ra03065g
    10.1039/c7ra03065g
  • 发表时间:
    2017-04
    2017-04
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Jun Chen
    Jun Chen
  • 通讯作者:
    Jun Chen
    Jun Chen
共 1 条
  • 1
前往

Jun Chen的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10696455
    10696455
  • 财政年份:
    2023
  • 资助金额:
    --
    --
  • 项目类别:
Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)
脂联素对血管性认知障碍和痴呆 (VCID) 的脑血管调节作用
  • 批准号:
    10542359
    10542359
  • 财政年份:
    2022
  • 资助金额:
    --
    --
  • 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
  • 批准号:
    10364171
    10364171
  • 财政年份:
    2022
  • 资助金额:
    --
    --
  • 项目类别:
Methods for microbiome compositional data
微生物组组成数据的方法
  • 批准号:
    10338342
    10338342
  • 财政年份:
    2022
  • 资助金额:
    --
    --
  • 项目类别:
Methods for microbiome compositional data
微生物组组成数据的方法
  • 批准号:
    10580718
    10580718
  • 财政年份:
    2022
  • 资助金额:
    --
    --
  • 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
  • 批准号:
    10188885
    10188885
  • 财政年份:
    2021
  • 资助金额:
    --
    --
  • 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
  • 批准号:
    10415152
    10415152
  • 财政年份:
    2021
  • 资助金额:
    --
    --
  • 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
  • 批准号:
    9471926
    9471926
  • 财政年份:
    2017
  • 资助金额:
    --
    --
  • 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
  • 批准号:
    10261320
    10261320
  • 财政年份:
    2017
  • 资助金额:
    --
    --
  • 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
  • 批准号:
    9697886
    9697886
  • 财政年份:
    2017
  • 资助金额:
    --
    --
  • 项目类别:

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Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
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