Anti-inflammatory signals and neurodegeneration

抗炎信号和神经退行性变

基本信息

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
项目类别：
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&apos 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&apos s Disease synucleinopathy trait transcriptome

项目摘要

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.

抽象的我们有强有力的证据表明神经免疫信号调节神经元功能和存活。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 独特表达。我们还发现了帕金森病 (PD) 中丢失的黑质致密部 (SNc) 神经元。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易感性迄今为止，还存在空白。了解神经炎症如何导致 PD 中 DA 神经元的选择性丧失。 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 IL-13 和 IL-13 的假设。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。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）影响的人类神经退行性变批准的药物抑制 IL-13Rα1 信号传导和新型铁死亡抑制剂 CMS121，以减少 IL- 最后，我们将在一种新的小鼠模型中进行体内实验，以测试 13 介导的损伤。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具有该突变的同源物导致小鼠中多巴胺能神经元更快地丧失。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。