2019-01-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/672832摘要：以小鼠模型發展思覺失調症的新治療靶點和治療藥物 摘要請見英文<br> Abstract: To date, many antipsychotics are antagonists of the dopamine D2 receptor (D2R). Because D2R binds with the A2A adenosine receptor (A2AR) and these two receptors antagonistically regulate each other upon activation, it has been proposed that stimulation of A2AR may suppress the hyperfunction of D2R in schizophrenia. Intriguingly, emerging evidence also indicates that some novel drugs and A2AR-related compounds have the potential to improve motor and cognitive functions in animal models. This is of great importance because D2R forms complex with not only A2AR but also the disrupted in schizophrenia 1 (DISC1, a risk gene of schizophrenia) and AKT1 (PKBα, another risk gene of schizophrenia). Both DISC1 and AKT1 modulate D2R signaling through forming DISC1-TRAX-A2AR and β-arrestin2/PP2A/AKT complexes, which have great impact on regulating downstream signaling pathways, including GSK3. Further understanding the role of D2R-DISC1-TRAX-A2AR and D2R/β-arrestin2/PP2A/AKT/GSK3 signaling complexes in the pathogenesis of schizophrenia would pave the way for the development of more effective antipsychotic drugs targeting at A2AR and new therapeutic targets to fulfill unmet medical needs with fewer side effects. Accordingly, in recent years, Dr. Chern’s lab at Academia Sinica had established a group of adenosine drugs that activate A2AR in the brain with no obvious peripheral side effects. Dr. Chern’s team recently reported a novel A2AR-TRAX-DISC1-GSK3β complex that may play a novel role in facilitating DNA repair (Chien et al., 2018; Chiu et al., 2015). Because A2AR activation negatively regulates D2R and that insufficient DNA repair has been implicated in schizophrenia, the newly identified A2AR-TRAX-DISC1-GSK3β complex may serve as a new and critical therapeutic target of schizophrenia. Importantly, the role of A2AR-TRAX axis in the regulation of the response of antipsychotic drugs has not been explored before. Meanwhile, Dr. Lai’s lab at National Taiwan University (NTU) has developed novel new chemical entities and tested GSK3 inhibitors for the treatment of schizophrenia in Akt1 and mutant mouse models, indicating the involvement of AKT in the control of GSK3 and the importance of β-arrestin2-PP2A-Akt-GSK3 signaling complexes in D2R signaling. In response to the urgent needs and the call of interdisciplinary efforts to study schizophrenia and develop new therapeutic agents, Dr. Chern’s group and Dr. Lai’s group team up together. Taking advantage of the Innovative Joint Program between Academia Sinica and NTU, we aim at characterizing a novel aspect of D2R signaling and identifying new therapeutic targets for the development of new antipsychotics. Our long-term goals for this project are (1) to investigate D2R-related complexes and signaling pathways and (2) identify a new class of compounds for the treatment of schizophrenia. We hypothesize that certain D2R-related proteins in the D2R-DISC1-TRAX-A2AR and D2R/β-arrestin2/PP2A/Akt signaling complexes can serve as a new and critical therapeutic target for the treatment of schizophrenia. Based on our recent findings and expertise in our labs, here we proposed 4 specific aims below. (1) To dissect the cross-talk between D2R and A2AR in the striatum of mouse models (2) Interactome analysis of DISC1 and TRAX (3) Evaluation of drug effects and in vivo efficacy in mouse models (4) Intellectual property (IP) application思覺失調症新治療靶點小鼠模式schizophrenianew therapeutic targetmouse models