2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642540摘要：泛自閉症障礙(autistic spectrum disorder)是一種發展性的心智障礙，其特徵包括社會互動、溝通的異常，以及重複性的行為。泛自閉症障礙的盛行率大約是一百六十分之一，但因缺少理想的實驗動物模式，目前尚未有對其主要症狀具有明顯療效的藥物問世。我們從本土病人的資料中，找出與自閉症相關的基因DLGAP2、FBXO25 與ARHGEF10作進一步的探討。DLGAP2分佈在神經元的突觸後，是穩固許多包括接受器、離子通道、訊息傳導物質等分子的骨架蛋白之一。FBXO25是一種在大腦中表現的蛋白，在SCF(SKP1-CUL1-F-box protein)-type E3連接酶(ligase)複合體中，扮演辨識受質的角色，與許多蛋白質的降解作用有關。ARHGEF10 是一種小型G蛋白質Rho的鳥苷酸交換因子(guanine nucleotide exchange factors)，與調節細胞骨架及樹突形態有關。我們目前已經產生了Dlgap2 與Fbxo25 的基因剔除小鼠在本計畫中我們要以這兩種小鼠作為自閉症的轉譯醫學動物模式。我們要一) 仔細地鑑定Dlgap2 與Fbxo25基因剔除鼠的行為、生理、解剖及生化上的異常，以及這些異常的發展進程。二) 探討影響其行為的分子與細胞學機制。三) 鑑定出致病的重要分子標靶。我們相信，研究這些自閉症相關的基因剔除鼠，將有助於我們了解自閉症的致病機制，及治療自閉症的藥物的開發。<br> Abstract: Autism spectrum disorders (ASDs) are characterized by prominent reciprocal social andcommunication impairments and restricted repetitive behaviors or interests. The prevalencefor ASDs is estimated about 1 in 160, however, there is no effective pharmaceutical treatmentfor the core symptoms of ASDs. It is largely due to the lack of ideal animal model to assist inunderstanding the pathogenesis of ASD. Based on our previous clinical study, we havechosen DAGAP2, FBXO25 and ARHGEF10 for further study. DLGAP2 belongs to thepostsynaptic adaptor proteins that associate with various synaptic components such asPSD-95, Shank, ionotropic and metabotropic glutamate receptors and might participate inthe organization of synapses and play roles in synaptic transmission and plasticity.FBXO25 is a substrate-recognition component of the SCF (SKP1-CUL1-F-boxprotein)-type E3 ligase complex. It is predominately expressed in the brain and may playroles in ubiquitination and protein degradation in neurons. ARHGEF10 is one of the Rhoguanine nucleotide exchange factors, which are important for Rho-dependent processessuch as regulation of cytoskeleton and dendritic morphology. Currently, Dlgap2 and Fbxo25knockout (KO) mice are generated. In this project, we will use these mice as animal modelsof ASD for translational medicine research. 1) We aim to characterize the phenotypes ofthese mice in behavioral, structural, physiological and biochemical aspects. 2) We will clarifythe pathophysiology of these genes in molecular, cellular and behavioral levels. 3) We are onthe way to identify the possible molecular targets of ASDs. Together, with the superb Dlgap2and Fbxo25 KO mouse models, our study will definitely advance our current understandingin the pathogenesis of autism and facilitate the development of new medicine.