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.

抽象的帕金森氏病（PD）是第二常见的神经退行性疾病，大约影响1％ 60岁以上的人口，仅在美国就报告了大约50,000例新案件。遗传研究已有鉴定出至少9个罕见的PD单基因原因和超过13个遗传基因座。但是，大多数PD案例仍然是未知的起源并被认为是由环境和遗传因素组合而成的。这些组合的识别仍然是一个重大挑战。在这里，我们建议检验以下假设，即一种组合由过敏反应表示（环境）和白介素13（IL-13Rα1）（遗传）的受体α1。我们的假设得到了人类的支持临床研究在提高过敏反应和对PD的易感性之间以及我们最近的易感性之间提供了牢固的联系发现过敏反应的关键调节剂IL-13和IL-13Rα1与人PD有关，并有助于神经元 PD小鼠模型的损失。如果成功，我们将确定过敏反应和IL-13系统为新的病原 PD的组件并将利用它们作为新的治疗靶标，以防止PD或减少其进展。抗过敏性疗法，包括特定的IL-13中和抗体，已经可以使用或正在开发中，这将减少基础研究，热剂的发展及其临床使用之间的时间延迟。另外，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 PD和神经退行性疾病的炎症和过敏。