Mechanisms involved in the Development Behavioural supersensitivity

参与发展行为超敏感性的机制

• 批准号: RGPIN-2017-06510
• 负责人: Mishra, Ram
• 金额: $ 2.04万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=659873
• 关键词: Mechanisms; involved; Development; Behavioural; supersensitivity

Short Term Objectives and Long Term Goals: The short term objectives of this program are to (1) gain an in-depth understanding of the molecular mechanisms involved in the development of behavioural supersensitivity following dopamine D2 receptor (D2R) antagonism and (2) to investigate the protective mechanisms of novel Peptide A designed in our lab. The long-term goals are to (3) investigate the changes in dopamine transporters and receptors induced by oxidative stress (OS) using brain imaging in live rats and (4) to enhance neuroprotection by developing novel microgels for targeted delivery of Peptide A to the brain.****Aims & Approaches****Short term 5 years: 1. To investigate the effects of novel Peptide A for neuroprotection against haloperidol-induced OS, various groups of rats will be treated with haloperidol, haloperidol + Peptide A, and inactive Peptide B for 28 days. Behavioural supersensitivity will be monitored by recording stereotyped behavior, vacuous chewing movements (VCMs) and locomotor activity. 2. To establish whether Peptide A prevents AIF translocation in striatopallidal neurons, striatoentopenduncular neurons, and astroglial cells, groups of rats will be treated with haloperidol, haloperidol + Peptide A, and vehicle solution for 28 days. At the end of treatment, brain regions will be dissected and labeled with specific antibodies for neurons and astroglial cells. 3. To establish whether there is an increase in glutamate release and decrease in GABA, rats will be treated as described above in Aim 2. Glutamate and GABA will be measured in live rats by microdialysis. 4. To investigate molecular mechanisms of Peptide A in cellular models, D2R-transfected human neuroblastoma SH SY5Y cells will be used to measure free radical formation, MEF2 and Nrf2 expression, and cell viability upon treatment with environmental toxin, paraquat, and haloperidol.****Long-term goals, beyond 5 years: 1. To determine whether intransal delivery of Peptide A prevents downregulation of dopamine transporters and D2Rs during oxidative stress using brain imaging. 2. To develop novel microgels for targeted delivery of Peptide A to the brain using our patented technology (Patent # 62/362,105,2016).****Novelty, Significance, and Impact:****This program uses technology ranging from cellular models to animal testing to advance our knowledge of oxidative stress and cell death. This research is essential as the mechanisms involved in cell death caused by certain compounds and environmental toxins are not known. Additionally, new insights into neuroprotection will help advance the development of more effective compounds. Combined with the production of novel microgels for enhanced targeted brain delivery, the patentable technology that will be developed in this project represents exciting opportunities for Canada to further increase its contribution to novel biological and engineering knowledge and techniques.***

短期目标和长期目标：该项目的短期目标是 (1) 深入了解多巴胺 D2 受体 (D2R) 拮抗作用后行为超敏反应的分子机制；(2) 研究我们实验室设计的新型肽 A 的保护机制。长期目标是 (3) 使用活体大鼠的脑成像研究氧化应激 (OS) 引起的多巴胺转运蛋白和受体的变化，以及 (4) 通过开发用于将肽 A 靶向递送至大脑的新型微凝胶来增强神经保护。****目标与方法****短期 5 年： 1. 研究新型肽 A 对氟哌啶醇诱导的 OS 的神经保护作用，各种 各组大鼠将接受氟哌啶醇、氟哌啶醇+肽A和无活性肽B治疗28天。通过记录刻板行为、空洞咀嚼运动（VCM）和运动活动来监测行为超敏性。 2.为了确定肽A是否阻止纹状体苍白球神经元、纹状体网桥神经元和星形胶质细胞中的AIF易位，将用氟哌啶醇、氟哌啶醇+肽A和载体溶液治疗各组大鼠28天。治疗结束时，大脑区域将被解剖并用神经元和星形胶质细胞的特异性抗体标记。 3.为了确定谷氨酸释放是否增加和GABA是否减少，将按照上述目标2中所述对大鼠进行治疗。将通过微透析在活体大鼠中测量谷氨酸和GABA。 4. 为了研究细胞模型中肽 A 的分子机制，将使用 D2R 转染的人神经母细胞瘤 SH SY5Y 细胞来测量自由基形成、MEF2 和 Nrf2 表达以及环境毒素、百草枯和氟哌啶醇处理后的细胞活力。****长期目标，超过 5 年： 1. 确定肽 A 的转运是否可以防止细胞因子的下调 使用脑成像技术研究氧化应激期间的多巴胺转运蛋白和 D2R。 2. 使用我们的专利技术（专利号 62/362,105,2016）开发新型微凝胶，用于将肽 A 靶向递送至大脑。****新颖性、意义和影响：****该计划使用从细胞模型到动物测试的技术来增进我们对氧化应激和细胞死亡的了解。这项研究至关重要，因为某些化合物和环境毒素引起的细胞死亡的机制尚不清楚。此外，对神经保护的新见解将有助于推动更有效化合物的开发。结合生产用于增强靶向大脑输送的新型微凝胶，该项目将开发的专利技术为加拿大进一步增加对新型生物和工程知识和技术的贡献提供了令人兴奋的机会。***