INTRABODY CONTROL OF EXPANDED REPEAT NEURODEGRATION

描述：该项目旨在开发小型，单链，内 抗多重复谷氨酰胺的细胞抗体(体内) 与某些神经系统疾病相关的蛋白质区域 作为亨廷顿氏症。这些体内的蛋白质将靶向 在组装后立即销毁，从而消除了其 有破坏性的影响，但不会对细胞造成损害。第一阶段 应用程序将寻求开发永生化细胞系 产生多重复谷氨酰胺蛋白的转基因小鼠。这个 第二个目标是生产和检测含有20个， 40和60个谷氨酰胺重复。他们正在试图理解 谷氨酰胺重复序列引起的构象变化，这可能 实现抗体结合。第三，将对大型图书馆进行筛选 针对合成的多肽来选择那些与 与多肽有亲和力的抗体。多次击球将会 以选择亲和力最高的抗体。实际 结合常数和离解常数将通过生物感官来评估 分析。最后的研究将测试体内的疗效。 从细胞系中去除多重复的谷氨酰胺蛋白 在项目早些时候建立的。初步研究表明， 提高这种靶向性体内是可能的。 建议的商业应用： 这些试剂及其衍生的药物可以用来治疗 由反复扩张引起的几种神经退行性疾病。

DESCRIPTION: This project seeks to develop small, single chain, intra- cellular antibodies (intrabodies) against the multi-repeat glutamine regions of proteins associated with certain neurological diseases such as Huntington's. These intrabodies would target the proteins for destruction immediately after they are assembled, thus eliminating their destructive effects, but not causing damage to the cell. The Phase I application would seek to develop immortalized cell lines from transgenic mice which produce multi-repeat glutamine proteins. The second aim is to produce and examine synthetic peptides containing 20, 40 and 60 glutamine repeats. They are seeking to understand conformational changes, induced by the glutamine repeats, which may effect antibody binding. Third, a large library would be screened against the synthetic peptides to select those phages linked to antibodies which have affinity for the peptides. Multiple pannings would be performed to select the highest affinity antibodies. Actual association and dissociation constants would be evaluated by biosensory analysis. The final studies would test the efficacy of the intrabodies at removing the multi-repeat glutamine proteins from the cell lines established earlier in the project. Preliminary studies indicate that it is possible to raise such targeted intrabodies. PROPOSED COMMERCIAL APPLICATION: These regents, and drugs derived from them, could be used to treat several neurodegenerative disorders caused by repeat expansions.