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Functional Outcomes of Interactions between an ASD-Relevant Gene and Air Pollution

ASD 相关基因与空气污染之间相互作用的功能结果

基本信息

批准号：
9116840
负责人：
Jill Lynn Silverman
金额：
$ 23.55万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116840
关键词：
Address Affect Air Air Pollutants Air Pollution Animal Model Applications Grants Archives Area Autistic Disorder Automobile Driving Behavior Behavioral Biological Markers Brain Breathing Characteristics Chemicals Child Consensus Control Animal Data Development Diagnostic Diesel Exhaust Disease Environment Environmental Risk Factor Epidemiologic Studies Exposure to Female Funding Future Gasoline Genes Genetic Genetic Predisposition to Disease Goals Growth Health Histologic Housing Human In Vitro Incidence Inflammatory Inhalation Exposure Institutes Intellectual functioning disability Intervention Knowledge Laboratories Lactation Life Link Mental Retardation and Developmental Disabilities Research Centers Modeling Mus Mutation Nervous system structure Neuraxis Neurodevelopmental Impairment Neurologic Neurons Outcome Pathology Performance Phenotype Pollution Predisposition Pregnancy Prevalence Process Protein Family Rattus Reflex action Regulation Reporting Research Research Personnel Risk Risk Factors Role Safety San Francisco Schools Severities Sex Characteristics Signal Transduction Signaling Molecule Source Symptoms Synapses Testing Time Toxicology Transgenic Organisms United States United States National Institutes of Health Vehicle Emissions air filter air sampling autism spectrum disorder behavioral impairment behavioral outcome behavioral study critical period developmental neurotoxicity disorder risk drug development early life exposure exhaust functional outcomes genetic risk factor improved in vivo innovation insight male member mouse model neurodevelopment neuroinflammation neuronal patterning neuropathology neurotoxic novel particle pollutant pre-clinical risk variant social communication synaptogenesis traffic-related air pollution trafficking

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) affects 1:68 children in the United States. There is now a consensus that multiple genetic loci combined with exposure(s) to unidentified environmental risk factors during neurodevelopment influence ASD susceptibility and symptom severity. Epidemiological studies consistently implicate traffic-related air pollution as an ASD risk factor, with the strongest associations found late in the gestational period and in early life. There is a paucity of research on the developmental neurotoxicity of air pollutant exposures in preclinical animal models, and to date, there are no reports testing the hypothesis that inhaled traffic-related pollution impairs behavior relevant to the ASD phenotype. Moreover, whether or not inflammatory consequences from vehicular emissions are related to ASD pathology is unknown. The objectives of this proposal are to analyze effects of exposure to traffic-related air pollution on ASD-relevant phenotypes. We hypothesize that exposure of the developing brain to toxic inhaled pollutants will cause neuroinflammation and interfere with normal patterns of neuronal connectivity and result in phenotypes associated with ASD. We further hypothesize that these histological and behavioral deficits will be exacerbated by one gene strongly implicated in ASD, ProSAP2/Shank3. To test this hypothesis, we will use an innovative exposure model that delivers real-time air samples from the Caldecott tunnel, near San Francisco. Polluted tunnel air will be delivered to subjects housed adjacent to the tunnel while control animals will be exposed to filtered air. We will also use a novel transgenic rat model of disrupted Shank3 expression. SHANK3 mutations are among the more prevalent and reliably replicated monogenic causes of ASD. These studies will clarify the role of driving on, living near, and attending schools adjacent to busy roadways in the onset and/or severity of ASD-relevant phenotypes. This project will leverage the NIH-funded MIND Institute Intellectual and Developmental Disabilities Research Center (IDDRC), of which the PI and Co-Investigator are members, to support the histological analyses and behavioral studies. These studies are needed to corroborate human studies linking developmental exposures to traffic-related air pollution to increased risk for ASD. The confirmation of traffic-related air pollution as an environmental risk factor for ASD will provide a rationale for controlling exposures to traffic-related air pollution during critical periods of neurodevelopment thereby reducing the incidence of ASD and/or decreasing the severity of symptoms. This proposal will develop a gene-environment approach that could be expanded to investigate other autism risk genes in future grant proposals.

描述（由申请人提供）：自闭症谱系障碍（ASD）影响1：68在美国的儿童。现在有一个共识，即多个遗传基因座结合暴露于未知的环境危险因素在神经发育影响ASD的易感性和症状的严重程度。流行病学研究一致表明，空气污染是ASD的危险因素，在妊娠后期和生命早期发现最强的相关性。在临床前动物模型中，缺乏关于空气污染物暴露的发育神经毒性的研究，迄今为止，还没有报告测试吸入的交通相关污染损害与ASD表型相关的行为的假设。此外，车辆排放的炎症后果是否与ASD病理学有关尚不清楚。这项提案的目的是分析暴露于交通相关的空气污染对ASD相关表型的影响。我们假设发育中的大脑暴露于有毒的吸入污染物会导致神经炎症，干扰神经元连接的正常模式，并导致与ASD相关的表型。我们进一步假设，这些组织学和行为缺陷将被一个与ASD密切相关的基因ProSAP 2/Shank 3所加剧。为了验证这一假设，我们将使用一种创新的暴露模型，该模型从旧金山弗朗西斯科附近的Caldecott隧道提供实时空气样本。将污染的隧道空气输送给饲养在隧道附近的受试者，而对照动物将暴露于过滤后的空气。我们还将使用一种新的破坏Shank 3表达的转基因大鼠模型。SHANK 3突变是ASD的更普遍和可靠复制的单基因原因之一。这些研究将阐明在忙碌道路附近开车、居住和上学在ASD相关表型的发病和/或严重程度中的作用。该项目将利用NIH资助的MIND研究所智力和发育障碍研究中心（IDDRC），PI和合作研究者是该中心的成员，以支持组织学分析和行为研究。需要这些研究来证实人类研究将发育暴露于交通相关空气污染与自闭症谱系障碍风险增加联系起来。确认交通相关的空气污染作为ASD的环境风险因素，将为在神经发育的关键时期控制暴露于交通相关的空气污染提供依据，从而降低ASD的发病率和/或降低症状的严重程度。该提案将开发一种基因-环境方法，可以在未来的拨款提案中扩展到调查其他自闭症风险基因。