Development of Par4 Peptide for Treatment of Alzheimers

用于治疗阿尔茨海默病的 Par4 肽的开发

• 批准号: 6556808
• 负责人: MARIE W WOOTEN
• 金额: $ 17.22万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556808
• 关键词: Alzheimer's disease; Escherichia coli; apoptosis; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; gene induction /repression; glutathione; inhibitor /antagonist; laboratory mouse; neural degeneration; neurophysiology; neuroprotectants; nuclear factor kappa beta; pathologic process; peptide chemical synthesis; protein isoforms; protein kinase C; protein protein interaction; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): The aim of this project will be to test the feasibility of developing and testing a novel peptide inhibitor that will specifically block Par4 interaction with the atypical protein kinase C isoform zeta. Par4 is a protein well established as a mediator of neuronal degeneration associated with the C pathogenesis of Alzheimer's disease. Clear evidence exists demonstrating that apoptotic stimuli cause Par4 to bind zetaPKC followed by cell death. Moreover, elevated Par4 suppresses the activity of the transcription factor nuclear factor kappa B, whose activity is required for transcription of prosurvival genes. The binding domain, which mediates the interaction between Par4 and zetaPKC has been mapped to the leucine zipper (LZ) domain (amino acids 265-332) of Par4. Moreover, deletion of Par4's LZ inhibits Par4's ability to induce apoptosis. Thus, the specific aims for this exploratory proposal will be: 1) to employ "peptide walking" to identify a specific peptide within the leucine zipper domain of Par4 that can be used to effectively disrupt interaction of zetaPKC with Par4; 2) to establish uptake of the peptide by cells in culture and delivery of the peptide to brain in vivo; 3) to establish functional inhibition of Par4 activity by the peptide inhibitor, and last; 4) to test the ability of the peptide to block neuronal cell death and restore normal function. Collectively these findings will lead to a significant breakthrough in the development of a designer therapeutic agent, which will protect neurons from the effects of Alzheimer's and other neurodegenerative diseases.

描述（由申请人提供）：该项目的目的是测试开发和测试一种新型肽抑制剂的可行性，该肽抑制剂将专门阻止PAR4与非典型蛋白激酶C同工ZETA的相互作用。 PAR4是一种蛋白质，作为与阿尔茨海默氏病的C发病机理相关的神经元变性介体。有明确的证据表明，凋亡刺激会导致PAR4结合ZetapkC，然后结合细胞死亡。此外，升高的PAR4抑制了转录因子核因子Kappa B的活性，Kappa B的活性是生存基因转录所必需的。介导PAR4和Zetapkc之间相互作用的结合结构域已映射到PAR4的亮氨酸拉链（LZ）结构域（氨基酸265-332）。此外，删除PAR4的LZ会抑制PAR4诱导凋亡的能力。因此，该探索性建议的具体目的是：1）使用“肽行走”来识别PAR4的亮氨酸拉链域内的特定肽，可用于有效破坏Zetapkc与PAR4的相互作用； 2）通过细胞在体内培养和递送到大脑的培养和递送中对肽的吸收； 3）建立对肽抑制剂对PAR4活性的功能抑制，最后； 4）测试肽阻断神经元细胞死亡并恢复正常功能的能力。这些发现集体将导致设计师治疗剂的发展取得重大突破，该剂将保护神经元免受阿尔茨海默氏病和其他神经退行性疾病的影响。