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Do allergens contribute to neurodegeneration?

过敏原会导致神经退行性变吗？

基本信息

批准号：
10190052
负责人：
BRUNO CONTI
金额：
$ 48.81万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190052
关键词：
Abbreviations Affect Age Allergens Allergic Reaction Allergic inflammation Amygdaloid structure Animal Model Animals Annual Reports Anti-Allergic Agents Basal Nucleus of Meynert Basic Science Behavioral Brain Brain region Case Study Cell Nucleus Cells Cessation of life Chronic Clinical Clinical Research Communities Development Disease Environmental Risk Factor Evaluation Exposure to Extrinsic asthma Genes Genetic Genetic study House Dust Mite Allergens Human Hypersensitivity Hypothalamic structure IL-13Ralpha1 IL13RA1 gene IL4 gene Idiopathic Parkinson Disease Immunohistochemistry In Situ Hybridization Individual Inflammation Inflammatory Interleukin-13 Interleukin-4 Intranasal Administration Knockout Mice Link Lipopolysaccharides LoxP-flanked allele Measures Mediating Modeling Molecular Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroimmune Neurons Neurotransmitters Oxidative Stress Parkinson Disease Pathogenicity Peripheral Pesticides Population Predisposition Process Production Pyroglyphidae Reactive Oxygen Species Role Signal Transduction Single Nucleotide Polymorphism Substantia nigra structure System Techniques Testing Time Toxin Tyrosine 3-Monooxygenase X Chromosome allergic response cholinergic neuron dopaminergic neuron dorsal motor nucleus experimental study genomic locus locus ceruleus structure male mitochondrial dysfunction mouse model neuron loss neuronal survival neutralizing antibody new therapeutic target noradrenergic novel olfactory bulb oxidative damage pars compacta piriform cortex prevent programmed cell death protein 1 protein misfolding raphe nuclei receptor response therapeutic development therapeutic target tool

项目摘要

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disorder and affects approximately 1% of the population over the age of 60, with about 50,000 new cases reported annually in the U.S. alone. Genetic studies have identified at least 9 rare, monogenic causes of PD and over 13 genetic loci. Yet, most PD cases remain of unknown origin and are believed to result from a combination of environmental and genetic factors. The identification of these combinations remains a major challenge. Here we propose to test the hypothesis that one combination is represented by allergic reaction (environmental) and the receptor α1 for the interleukin 13 (IL-13Rα1) (genetic). Our hypothesis is supported by a human clinical study providing a strong link between heightened allergic response and susceptibility to PD, as well as by our recent finding that pivotal regulators of allergic reactions, IL-13 and IL-13Rα1, are linked to human PD and contribute to neuronal loss in mouse models of PD. If successful, we will identify allergic reactions and the IL-13 system as novel pathogenic components of PD and will utilize them as novel therapeutic targets to prevent PD or reduce its progression. Anti-allergic therapies, including specific IL-13 neutralizing antibodies, are already available or are under development, which will reduce the time delay between basic research, development of therapeutic agents, and their clinical use. In addition, the animal model will provide a new experimental tool for the scientific community to further understand the role of inflammation and allergy in PD and neurodegenerative diseases.

摘要帕金森病（PD）是第二常见的神经退行性疾病，影响约1%的 60岁以上的人群，仅美国每年就报告约50，000例新病例。遗传学研究确定了至少9种罕见的PD单基因病因和超过13个遗传位点。然而，大多数PD病例仍然来源不明并且被认为是环境和遗传因素的组合造成的。这些组合的识别仍然是一个重大挑战。在这里，我们建议测试的假设，一个组合是代表过敏反应白细胞介素13受体α1（IL-13 R α1）（遗传）。我们的假设得到了一个人类的支持一项临床研究提供了增强的过敏反应和对PD的易感性之间的强有力的联系，以及我们最近的发现过敏反应的关键调节因子IL-13和IL-13 R α1与人类PD有关，并有助于神经元 PD小鼠模型中的损失。如果成功，我们将确定过敏反应和IL-13系统作为新的致病因素， PD的组成部分，并将利用它们作为新的治疗靶点，以预防PD或减少其进展。抗过敏包括特异性IL-13中和抗体在内的治疗方法已经可用或正在开发中，缩短基础研究、治疗药物开发及其临床应用之间的时间延迟。此外该动物模型将为科学界提供一种新的实验工具，以进一步了解炎症和变态反应。