Anti-inflammatory signals and neurodegeneration

抗炎信号和神经退行性变

• 批准号: 10928425
• 负责人: BRUNO CONTI
• 金额: $ 64.61万
• 依托单位: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10928425
• 关键词: Abbreviations; Ablation; Address; Affect; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Apoptosis; Brain; Cell Death; Cell Line; Cells; Chemosensitization; Chronic; Complex; Data; Deposition; Development; Diagnosis; Disease; Dopaminergic Cell; FDA approved; Fatty-acid synthase; Generations; Genes; Genetic; Genetic Polymorphism; Homologous Gene; Human; Hydrogen Peroxide; IL-13Ralpha1; IL13RA1 gene; In Situ Hybridization; In Vitro; Individual; Inflammatory; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Iron; Knockout Mice; Laboratories; Leucine; Linkage Disequilibrium; Lipid Peroxides; Lipopolysaccharides; LoxP-flanked allele; Mediating; Microglia; Midbrain structure; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neurons; Odds Ratio; Oxidants; Oxidative Stress; Parkinson Disease; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Peroxides; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Predisposition; Proline; Publishing; Reactive Oxygen Species; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Substantia nigra structure; System; Testing; Toxic effect; Transgenic Mice; Tyrosine 3-Monooxygenase; Variant; Virus; Work; X Chromosome; alpha synuclein; cytokine; cytotoxic; dopaminergic neuron; early onset; experimental study; gain of function; genetic variant; glial activation; in vivo; induced pluripotent stem cell; inhibitor; locus ceruleus structure; male; mitochondrial dysfunction; mouse model; mutant; neuroinflammation; neuron loss; neuroprotection; neurotoxicity; noradrenergic; novel; novel therapeutic intervention; originality; oxidative damage; pars compacta; patient subsets; phase I trial; prevent; receptor; sporadic Parkinson' s Disease; synucleinopathy; trait; transcriptome

Abstract Neuroimmune signals regulate neuronal function and survival. We have strong evidence indicating that activation of the heterodimeric interleukin-13 receptor alpha 1/interleukin-4 receptor alpha (IL-13Rα1/IL-4Rα) complex in midbrain dopaminergic (DA) neurons affects their viability. In the brain, IL-13Rα1/IL-4Rα is uniquely expressed on the neurons of the substantia nigra pars compacta (SNc) that are lost in Parkinson’s disease (PD). We also showed that interleukin 13 (IL-13), produced during neuroinflammation by microglia and neurons, can modulate the activity of dopaminergic cells and increase their susceptibility to oxidative damage. To date, there is a gap in understanding how neuroinflammation contributes to the selective loss of DA neurons in PD. Having established that activation of IL-13Rα1 signaling can affect the survival of dopaminergic neurons during neuroinflammation, in the present application we wish to address this gap. Specifically, we wish to test the hypothesis that IL-13 and neuronal IL-13Rα1 cause damage by stimulating a regulated cell death pathway called ferroptosis. We also wish to determine to what extent IL-13 and IL-13Rα1 contribute to neurodegeneration in a mouse model of alpha- synucleinopathy (α-Syn), a hallmark trait of PD that is associated with neuroinflammation and oxidative damage. This will help us determine whether targeting IL-13Rα1 signaling might be a viable approach to slow neurodegeneration in humans affected by α-synucleinopathy such as PD. The ability of ruxolitinib, an FDA- approved drug that inhibits IL-13Rα1 signaling and that of the novel ferroptosis inhibitor CMS121, to reduce IL- 13-mediated damage in vivo will also be tested. Finally, we propose in vivo experiments un a novel mouse model to test the hypothesis that a rare genetic variant of IL-13 found in individuals diagnosed with early-onset PD can contribute to more rapid loss of dopaminergic neurons in a mouse with the homologue of this mutation. If successful, these experiments will provide strong support for the hypothesis that IL-13 and IL-13Rα1 are novel targets for preventing PD or slowing its progression, at least in a sub-set of PD patients.

抽象的 神经免疫信号调节神经元功能和存活。我们有强有力的证据表明激活 异二聚体白介素 13 受体 α 1/白细胞介素 4 受体 α (IL-13Rα1/IL-4Rα) 复合物 中脑多巴胺能 (DA) 神经元影响其活力。在大脑中，IL-13Rα1/IL-4Rα 独特地表达于 帕金森病 (PD) 中丢失的黑质致密部 (SNc) 神经元。我们还展示了 小胶质细胞和神经元在神经炎症过程中产生的白细胞介素 13 (IL-13) 可以调节 多巴胺能细胞的活性并增加其对氧化损伤的敏感性。迄今为止，还存在着差距 了解神经炎症如何导致 PD 中 DA 神经元的选择性丧失。已建立 IL-13Rα1信号的激活可以影响神经炎症期间多巴胺能神经元的存活， 在本申请中，我们希望解决这一差距。具体来说，我们希望检验以下假设：IL-13 和 神经元 IL-13Rα1 通过刺激称为铁死亡的受调节细胞死亡途径造成损伤。我们也祝愿 确定 IL-13 和 IL-13Rα1 对 α- 小鼠模型神经变性的影响程度 突触核蛋白病 (α-Syn) 是 PD 的一个标志性特征，与神经炎症和氧化损伤相关。 这将帮助我们确定靶向 IL-13Rα1 信号传导是否是减缓 受 α-突触核蛋白病（例如 PD）影响的人类神经变性。 FDA 批准的鲁索替尼 (ruxolitinib) 的能力 批准的药物抑制 IL-13Rα1 信号传导和新型铁死亡抑制剂 CMS121，以减少 IL- 13介导的体内损伤也将被测试。最后，我们提出了一种新型小鼠模型的体内实验 检验以下假设：在诊断为早发性帕金森病的个体中发现的 IL-13 的罕见遗传变异可以 导致具有该突变同源物的小鼠中多巴胺能神经元更快地丧失。如果 成功的话，这些实验将为IL-13和IL-13Rα1是新颖的假设提供强有力的支持 至少在一部分帕金森病患者中预防帕金森病或减缓其进展的目标。