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.

抽象的神经免疫信号调节神经元功能和存活。我们有强烈的证据表明激活杂二聚体白介素-13受体α1/白介素-4受体α（IL-13Rα1/IL-4Rα）在中脑多巴胺能（DA）神经元影响其生存能力。在大脑中，IL-13Rα1/IL-4Rα在在帕金森氏病（PD）中丢失的黑质Nigra Pars Commacta（SNC）的神经元。我们也表明小胶质细胞和神经元在神经炎症期间产生的白介素13（IL-13）可以调节多巴胺能细胞的活性并增加了其对氧化损伤的敏感性。迄今为止，存在差距了解神经炎症如何导致PD中DA神经元的选择性丧失。建立了 IL-13Rα1信号的激活会影响神经炎症过程中多巴胺能神经元的存活，在本应用程序中，我们希望解决此差距。具体而言，我们希望检验IL-13和神经元IL-13Rα1通过刺激称为铁毒性的调节细胞死亡途径而造成损害。我们也希望确定IL-13和IL-13Rα1在多大程度上有助于α-小鼠模型中的神经变性肌醇（α-Syn），一种与神经炎症和氧化损伤有关的标志性特征。这将有助于我们确定靶向IL-13Rα1信号传导是否可能是一种可行的方法人类的神经变性受PD等α-突触核酸的影响。 ruxolitinib的能力，fda- 批准抑制IL-13Rα1信号的药物和新型的铁铁抑制剂CMS121的药物，以减少IL- 还将测试13个介导的体内损伤。最后，我们提出了一个新型的小鼠模型的体内实验为了检验以下假设：在被诊断为早发PD的个体中发现的罕见的IL-13遗传变异通过这种突变的同源物，在小鼠中更快地丧失了多巴胺能神经元。如果成功，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PD患者的子集中，预防PD或减慢其进展的靶标。