权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

GI Endotoxin as an Environmental Trigger in an alpha-Synuclein Transgenic Mouse

胃肠道内毒素作为 α-突触核蛋白转基因小鼠的环境触发因素

基本信息

批准号：
8305727
负责人：
ROBERT L NUSSBAUM
金额：
$ 38.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-06 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305727
关键词：
Affect Age Age-Months Alpha-Synuclein transgenic mouse Animal Model Animals Artificial Chromosomes Autonomic Dysfunction Autonomic nervous system Autopsy Bacteria Bacterial Toxins Brain Brain Stem Breathing Catecholamines Cell model Central Nervous System Diseases Characteristics Chemical Agents Complex Corpus striatum structure Defect Dementia Development Disease Drug Implants Endotoxins Engineering Enteral Enteric Nervous System Environmental Exposure Environmental Risk Factor Epidemiology Equilibrium Escherichia coli Etiology Exposure to Family Family Study Functional disorder Gastrointestinal tract structure Genetic Genetic Predisposition to Disease Genotype Goals Health Heavy Metals Human Individual Inflammation Inflammatory Inherited Intervention Intestines Label Lipopolysaccharides Measures Mental Depression Messenger RNA Microarray Analysis Microbe Midbrain structure Modeling Motor Movement Disorders Mus Mutation Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurologic Olfactory Nerve Oral Oral Administration Parkinson Disease Parkinsonian Disorders Pathogenesis Pathology Patients Penetration Pesticides Plasma Predisposition Prevention Process Proteins Recombinant DNA Reporting Research Risk Role Rotenone SNCA gene Series Severities Staging Substantia nigra structure Symptoms Testing Time Toxic Environmental Substances Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Twin Multiple Birth Twin Studies United States Variant Virus Diseases absorption alpha synuclein base cell motility cohort cytokine density disability dopaminergic neuron environmental agent gastrointestinal gastrointestinal function genetic association human disease implantable device inflammatory marker mutant nervous system disorder neuron loss neurotoxic neurotoxicity overexpression synuclein

项目摘要

DESCRIPTION (provided by applicant): Parkinson Disease (PD) is a common neurodegenerative disease affecting ~1 million people in the United States. While loss of substantia nigra dopaminergic neurons is primarily responsible for the characteristic parkinsonian movement disorder, non-motor disabilities including dementia, depression, gastrointestinal dysfunction, and autonomic instability arise from neurodegeneration elsewhere in the central, enteric and autonomic nervous systems. The cause of most PD is unknown despite decades of research. Family studies, twin studies, and genetic association studies in Parkinson disease (PD) support the view that PD is a complex systemic nervous system disorder caused by one or more environmental agents acting on genetically vulnerable individuals. The genetic predisposition can be strong, as in the rare, familial forms of PD caused by missense or copy number mutations in the 1-synuclein gene (SNCA), or subtle, as in the more common sporadic disease, where genetic association studies indicate that polymorphic variants at the SNCA locus contribute to genetic predisposition. Epidemiological and experimental observations have suggested many different environmental agents may contribute to the development of PD. These include viral infection, heavy metals, bacterial toxins, microbe-induced inflammation, and chemical agents including pesticides. The balance between genetic predisposition and environmental insult is likely to be different depending on the strength of the predisposition. The intensity of environmental exposure required to cause disease is likely inversely related to the degree of genetic vulnerability: the greater the genetic susceptibility, the less the environmental exposure required and the more apparently heritable the disease will appear to be. Exposure to the environmental agents implicated in PD is probably via the gastrointestinal (GI) tract (although inhalation exposing the olfactory nerves is also possible), suggesting that the enteric nervous system (ENS), which would be on the front lines of exposure to these environmental agents, might be affected early in the disease. Indeed, GI dysfunction is well documented to occur years to decades before the motor signs in PD patients. Braak and his colleagues reported that the youngest individuals in their large autopsy series showed pathological changes of PD only in the enteric nervous system (ENS), while PD pathology in the CNS appeared at older ages, affecting predominantly the brain stem, as well as in the ENS. Ultimately, CNS pathology in the midbrain (including substantia nigra) and cortex was seen in still older individuals. We propose to test the hypothesis that exposure of genetically predisposed mice to pathogenic environmental exposures through the GI tract will model PD and that early ENS dysfunction not only temporally precedes CNS dysfunction but actually contributes causally to it by increasing the exposure to these agents. We have developed a series of transgenic mice engineered to mimic genetically vulnerable individuals with familial PD due to SNCA mutations. These mice overexpress either wildtype or mutant (A53T and A30P) human 1-synuclein from a P1 artificial chromosome containing the human SNCA locus. Mice expressing either of the two mutant, but not wildtype, 1-synucleins have ENS dysfunction as early as 3 months of age, with prolonged Gl transit time and decreased colonic motility, but minimal CNS dysfunction and CNS neuronal loss. We will expose these transgenic animals to gram-negative endotoxin and rotenone, two agents frequently considered as environmental toxins most strongly implicated in PD. We will ask whether the enteric nervous system defect in our 1Syn transgenic models will (1) cause changes in distribution and composition of gut flora and exposure to intestinal bacteria, (2) enhance the absorption of endotoxin leading to systemic inflammatory effects and neurological defects, and (3) increase absorption and neurotoxicity of rotenone, a pesticide previously shown in cellular and animal models to cause neurodegeneration. PUBLIC HEALTH RELEVANCE: Evidence is accumulating that environmental exposures in individuals genetically predisposed to Parkinson disease are critical in the development of the disease. The applicant wants to know if mice, engineered to mimic the genetic make-up of humans with a form of hereditary Parkinson disease, are at significantly increased risk for developing a mouse equivalent of Parkinson disease when exposed through their gastrointestinal tract to two different environmental agents thought to have a role in causing human PD: endotoxin made by normal bacteria in the gut and the commonly used pesticide rotenone. The ultimate goal is to study in detail the role of gastrointestinal exposure to environmental agents in the development of neurodegeneration in a model of the natural human disease. By understanding the disease process, we can identify points at which interventions could slow or stop its progression.

描述(申请人提供)：帕金森病(PD)是一种常见的神经退行性疾病，在美国约有100万人患病。虽然黑质多巴胺能神经元的丢失是帕金森氏症典型运动障碍的主要原因，但包括痴呆、抑郁、胃肠功能障碍和自主神经不稳定在内的非运动障碍是由于中枢、肠道和自主神经系统其他部位的神经变性引起的。尽管进行了数十年的研究，但大多数帕金森病的病因尚不清楚。帕金森病(PD)的家系研究、双生子研究和遗传关联研究支持PD是一种复杂的全身性神经系统疾病的观点，该疾病是由一个或多个环境因素作用于遗传易感个体而引起的。遗传易感性可能很强，如罕见的家族性帕金森病，由1-突触核蛋白基因(SNCA)的错义或拷贝数突变引起，或微妙，如在更常见的散发性疾病中，遗传关联研究表明，SNCA基因座的多态变异有助于遗传易感性。流行病学和实验观察表明，许多不同的环境因素可能有助于帕金森病的发展。这些包括病毒感染、重金属、细菌毒素、微生物引起的炎症以及包括杀虫剂在内的化学制剂。遗传易感性和环境侮辱之间的平衡可能会有所不同，这取决于易感性的强度。致病所需的环境暴露强度可能与遗传脆弱性的程度成反比：遗传易感性越大，所需的环境暴露就越少，疾病看起来就越容易遗传。与帕金森病有关的环境因素的暴露可能是通过胃肠道(GI)途径(尽管吸入暴露嗅神经也是可能的)，这表明处于这些环境因素暴露的第一线的肠道神经系统(ENS)可能在疾病的早期受到影响。事实上，胃肠道功能障碍在帕金森病患者出现运动体征之前几年到几十年就已经有了很好的记录。Braak和他的同事报告说，在他们的大型尸检系列中，最年轻的人只在肠道神经系统(ENS)显示帕金森病的病理变化，而中枢神经系统的帕金森病病理出现在较年长的人，主要影响脑干，以及ENS。最终，中脑(包括黑质)和皮质的中枢神经系统病理在更年长的个体中被看到。我们建议检验这样一种假设，即通过胃肠道将致病环境暴露于遗传易感小鼠将建立PD模型，并且早期ENS功能障碍不仅暂时先于中枢神经系统功能障碍，而且实际上通过增加对这些药物的暴露而起到因果作用。我们已经开发了一系列转基因小鼠，旨在模拟因SNCA突变而患有家族性帕金森病的遗传脆弱个体。这些小鼠过度表达野生型或突变型(A53T和A30P)人1-突触核蛋白，这些人1-突触核蛋白来自包含人类SNCA基因的P1人工染色体。表达这两个突变型但不是野生型1-突触核蛋白的小鼠早在3个月大时就出现了ENS功能障碍，Gl传递时间延长，结肠动力减弱，但中枢神经系统功能障碍和中枢神经系统神经元丢失很少。我们将把这些转基因动物暴露在革兰氏阴性内毒素和鱼藤酮中，这两种物质通常被认为是与帕金森病关系最密切的环境毒素。我们将询问我们的1Syn转基因模型中的肠道神经系统缺陷是否会(1)引起肠道菌群分布和组成的改变以及肠道细菌的暴露，(2)增加内毒素的吸收，导致全身炎症效应和神经缺陷，以及(3)增加鱼藤酮的吸收和神经毒性，鱼藤酮是一种以前在细胞和动物模型中显示的导致神经退化的杀虫剂。公共卫生相关性：越来越多的证据表明，遗传上易患帕金森病的人暴露在环境中对疾病的发展至关重要。申请者想知道，经过改造以模仿患有某种遗传性帕金森病的人类的基因构成的小鼠，如果通过胃肠道暴露于两种被认为在导致人类帕金森氏病中起作用的不同环境因素，是否会显著增加患上相当于帕金森病的小鼠的风险：肠道中正常细菌产生的内毒素和常用的杀虫剂鱼藤酮。最终目标是在自然人类疾病的模型中详细研究胃肠道暴露于环境因素在神经退行性变发展中的作用。通过了解疾病过程，我们可以确定干预措施可以减缓或阻止其进展的点。