Behavioral and Neural Deterioration in Drosophila

果蝇的行为和神经退化

• 批准号: 6355949
• 负责人: MICHAEL B MCKEOWN
• 金额: $ 7.89万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355949
• 关键词: Drosophilidae; aging; arthropod genetics; behavioral /social science research tag; behavioral genetics; developmental genetics; developmental neurobiology; ethology; gene expression; gene mutation; neural degeneration; neurogenetics; reproduction

This proposal describes the first steps in understanding the genetic, molecular and cellular basis of one model of age-dependent behavioral and neural degeneration. This has become highly relevant to human health and quality of life as advanced medicine now allows many people to survive for years with significant behavioral and cognitive deficits. The entree into these studies is the recent observation that mutations in the Drosophila kelch gene lead to age-dependent deficits in mating success, sexual receptivity, and body control without significantly reduced viability. The relevance of these studies is increased by the identification of nervous-system-expressed homologs of kelch in humans. The long term goal of this project is to understand the cellular basis of neural and behavioral defects associated with kelch mutations, to link this to the molecular action of Kelch, to use appropriate manipulations of kelch mutations to screen for addition proteins interacting with Kelch in maintenance of neural function, and to model the potential action of wild type and mutant versions of the human Kelch-like proteins. In this pilot project special emphasis will be given to laying the necessary foundation for the more ambitious long term goals. Molecularly mapped nonsense and missense mutations will be carefully characterized for severity and time course of multiple behavioral phenotypes. This will determine the array of possible kelch phenotypes and the consequences of alterations in defined protein domains. In parallel with the characterization of age- dependent behavioral phenotypes, age-associated abnormalities in the CNS, neuromuscular system, and visual system will be examined, both in the CNS as a whole and in defined subsets of neurons or glia. Characterization of alterations in the CNS or peripheral nervous system will be correlated with expression patterns for Kelch as determined by RNA hybridization and Kelch-specific antibodies. Reagents for later studies, including targeted expression of Kelch, GFP-Kelch and corresponding human proteins in animals or in culture, and examination of small groups of Kelch mutant cells will be constructed.

这项建议描述了理解一种年龄相关行为和神经退化模型的遗传、分子和细胞基础的第一步。这已经成为与人类健康和生活质量高度相关的问题，因为先进的医学现在允许许多有严重行为和认知缺陷的人存活多年。这些研究的主要内容是最近的观察到，果蝇kelch基因的突变会导致交配成功、性接受和身体控制方面的年龄相关性缺陷，而不会显著降低生存能力。通过鉴定人类海带的神经系统表达的同源物，这些研究的相关性增加了。该项目的长期目标是了解与Kelch突变相关的神经和行为缺陷的细胞基础，将其与Kelch的分子作用联系起来，使用Kelch突变的适当操作来筛选与Kelch相互作用的额外蛋白以维持神经功能，并对人类Kelch样蛋白的野生型和突变型的潜在作用进行建模。在这一试点项目中，将特别强调为更雄心勃勃的长期目标奠定必要的基础。分子图谱上的无义和错义突变将仔细描述多种行为表型的严重性和时间进程。这将决定一系列可能的kelch表型和已定义蛋白质结构域变化的后果。在描述与年龄相关的行为表型的同时，还将检查中枢神经系统、神经肌肉系统和视觉系统中与年龄相关的异常，包括整个中枢神经系统和确定的神经元或神经胶质细胞亚群。中枢神经系统或周围神经系统改变的特征将与通过RNA杂交和Kelch特异性抗体确定的Kelch的表达模式相关。以后的研究将建立试剂，包括在动物或培养中靶向表达Kelch、GFP-Kelch和相应的人类蛋白，以及检测Kelch突变细胞的小群体。