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（由适用提供）：自闭症谱系障碍（ASD）影响美国的1:68儿童。现在有一个共识，在神经发育过程中，多个遗传基因座与对统一环境风险因素的接触会影响ASD的敏感性和症状严重程度。流行病学研究始终暗示与交通有关空气污染是ASD危险因素，在妊娠期和早期生命后期发现了牢固的关联。关于临床前动物模型中空气污染物暴露的发育神经毒性的研究很少，迄今为止，尚无报告检验的假设，即遗传交通相关的污染会损害与ASD表型相关的行为。此外，尚不清楚车辆排放的炎症后果是否与ASD病理有关。该提案的目标是分析暴露于交通相关的空气污染对与ASD相关的表型的影响。我们假设发育中的大脑暴露于有毒的遗传污染物会导致神经炎症和干扰神经元连通性的正常模式，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定义将被一个与ASD，Prounap2/shank3强的基因加剧。为了检验这一假设，我们将使用一种创新的曝光模型，该模型可从旧金山附近的Caldecott隧道提供实时空气样本。污染的隧道空气将交付给隧道附近的受试者，而控制动物将暴露于过滤的空气中。我们还将使用破坏的shank3表达的新型转基因大鼠模型。 Shank3突变是ASD的更为普遍和可靠的复制单基因原因。这些研究将阐明在与ASD相关的表型的发作和/或严重程度中，驾驶，居住在附近并就读于繁忙道路的学校的作用。该项目将利用NIH资助的思想和发展障碍研究中心（IDDRC），其中PI和共同投资者是成员，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与交通相关的空气污染联系起来，以增加ASD的风险。确认与交通相关的空气污染是ASD的环境风险因素，将为控制与交通相关的空气污染的暴露在神经发育的关键时期，从而减少ASD的事件和/或降低症状的严重程度。该提案将开发一种基因环境方法，可以扩展，以调查未来赠款建议中其他自闭症风险基因。