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

 描述(由申请人提供)：自闭症谱系障碍(ASD)在美国影响1：68的儿童。现已达成共识，即多个基因座结合神经发育过程中暴露于未知环境风险因素(S)会影响自闭症的易感性和症状严重程度。流行病学研究一直表明与交通有关 空气污染是自闭症的危险因素，在妊娠晚期和生命早期发现的相关性最强。在临床前动物模型中，关于空气污染物暴露的发育神经毒性的研究很少，到目前为止，还没有报告验证吸入交通相关污染损害与ASD表型相关的行为这一假说。此外，车辆排放的炎性后果是否与ASD的病理相关尚不清楚。这项建议的目的是分析暴露于与交通相关的空气污染对ASD相关表型的影响。我们假设，将发育中的大脑暴露在有毒的可吸入污染物中会引起神经炎症，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，与ASD密切相关的一个基因ProSAP2/Shank3将加剧这些组织和行为缺陷。为了验证这一假设，我们将使用一种创新的暴露模型，该模型从旧金山附近的Caldecott隧道提供实时空气样本。受污染的隧道空气将被输送到隧道附近的受试者手中，而对照动物将暴露在过滤后的空气中。我们还将使用一种新的转基因大鼠模型来破坏Shank3的表达。SHANK3突变是ASD更普遍和更可靠的单基因复制原因之一。这些研究将阐明在繁忙道路附近开车、居住和上学在ASD相关表型的发病和/或严重程度中所起的作用。该项目将利用NIH资助的精神研究所智力和发育障碍研究中心(IDDRC)，PI和联合调查员是该中心的成员，以支持组织分析和行为研究。需要这些研究来证实人类研究将与交通相关的空气污染与ASD风险增加联系起来。确认与交通有关的空气污染是自闭症的环境风险因素，将为在神经发育的关键时期控制与交通有关的空气污染的暴露提供理由，从而减少自闭症的发生率和/或减轻症状的严重程度。这项提案将开发一种基因-环境方法，该方法可以在未来的拨款提案中扩展到研究其他自闭症风险基因。

 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.