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.

该建议描述了一种了解一个年龄依赖性行为和神经变性模型的遗传，分子和细胞基础的第一步。现在，这与人类健康和生活质量高度相关，因为高级医学现在使​​许多人能够在行为和认知障碍的严重缺陷中生存多年。这些研究的意识是最近的观察结果，即果蝇基因中的突变导致年龄依赖性缺陷在交配成功，性接受和身体控制方面，而没有显着降低生存能力。通过鉴定人类Kelch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，以将其与Kelch的分子作用联系起来，以使用Kelch突变的适当操纵来筛选与Kelch在维持神经功能方面与Kelch相互作用的蛋白质，并在维持神经功能方面相互作用，并模拟野外类型和突变版本的蛋白质蛋白质的潜在作用。在这个试点项目中，将特别强调为更雄心勃勃的长期目标奠定必要的基础。分子映射的胡说八道和错义突变将以多种行为表型的严重程度和时间过程进行仔细的特征。 这将确定可能的Kelch表型的阵列以及定义蛋白质结构域改变的后果。 与依赖年龄相关的行为表型的表征，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，无论是在整个中枢神经系统中还是在神经元或神经元的定义子集中。通过RNA杂交和Kelch特异性抗体确定的CNS或周围神经系统变化的表征将与Kelch的表达模式相关。以后研究的试剂，包括靶向kelch，GFP-kelch的靶向表达以及动物或培养中相应的人蛋白，以及对小组Kelch突变细胞的检查。