SCREENING FOR DRUGS IN A DROSOPHILA TRANSGENIC MODEL

在果蝇转基因模型中筛选药物

• 批准号: 6798018
• 负责人: GEORGE R JACKSON
• 金额: $ 19.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798018
• 关键词: Alzheimer' s disease; Drosophilidae; antioxidants; bioassay; confocal scanning microscopy; cysteine endopeptidases; disease /disorder model; drug screening /evaluation; enzyme inhibitors; genetically modified animals; immunocytochemistry; microtubule associated protein; neural degeneration; neurofibrillary tangles; neuropathology; phosphorylation; protease inhibitor; scanning electron microscopy; transmission electron microscopy; western blottings

Mutations in the microtubule-associated protein tau occur in some cases of inherited frontotemporal dementia (FTD), demonstrating that tau abnormalities can cause neurodegeneration. Many FTD mutations occur in regulatory elements that alter splicing and thereby expression of tau isoforms, rather than tau coding sequence. One of the hallmark neuropathologic features of AIzheimer's disease (AD) is the neurofibrillary tangle (NFT), which contains hyperphosphorylated tau. Characterization of the events that modify tau-associated neurodegenerative processes is critical for understanding the pathophysiology of AD, as well as FTD and related diseases, such as progressive supranuclear palsy and corticobasal degeneration, and for the development of therapeutics. In order to test the hypothesis that neurodegeneration can be caused by aberrant expression of wild-type tau, the longest isoform of human tau was overexpressed in the fruit fly, producing degeneration of the eye and underlying brain, but failing to produce neurofibrillary tangles. However, tau phosphorylation by co-expression of shaggy, the Drosophila homologue of glycogen synthase kinase (GSK)-3beta, an important tau kinase in vitro, produced a more severely degenerated eye, as well as lesions resembling NFT (Jackson, G.R., et al. (2002): Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34: 509-519). Here, we propose to test selected kinase inhibitors, caspase inhibitors, and antioxidants for their ability to suppress the dual tau + shaggy bioassay phenotype. We also will test a library of commercially available, FDA-approved compounds (Microsource Discovery Systems) for their ability to suppress the external eye phenotype of tau + shaggy flies. Subsequently, we will determine the effects of identified compounds on cell death and conformation and solubility of tau. This project contributes to the commitment of the UCLA Alzheimer's Disease Research Center (ADRC) to foster research that will lead to identification of disease-modifying therapies for AD and related conditions. The Project will interact with Project 2 assessing similar compounds in transgenic mice.

微管相关蛋白tau中的突变发生在某些情况下 额颞痴呆（FTD），表明tau异常会导致神经变性。许多FTD突变发生在改变剪接并从而表达tau同工型而不是TAU编码序列的调节元件中。 Aizheimer病（AD）的标志性神经病理学特征之一是神经纤维缠结（NFT），其中含有高磷酸化的tau。修改TAU相关神经退行性过程的事件的表征对于理解AD的病理生理以及FTD及其相关疾病（例如进行性性核上麻痹和皮质性生蛋白变性，以及治疗剂的发育）至关重要。为了检验神经退行性的假设可能是由异常表达野生型Tau引起的，人类tau的最长同工型在果蝇中过表达，从而产生眼睛的变性 大脑的基础，但无法产生神经原纤维缠结。然而，tau磷酸化是通过毛毛发的共表达，糖原合酶激酶的果蝇同源物（GSK）-3Beta是一种重要的tau激酶，在体外重要的tau激酶，产生了更严重的退化性的眼睛，以及nft nft（Jackson，G.R。wild。成分并在果蝇中产生神经纤维病理学。在这里，我们建议测试选定的激酶抑制剂，caspase抑制剂和抗氧化剂，以抑制双重tau +毛茸茸的生物测定表型。我们还将测试由FDA批准的化合物（Microsource Discovery Systems）的库，以抑制Tau +毛茸茸的苍蝇的外眼表型的能力。随后，我们将确定已鉴定化合物对TAU细胞死亡以及构象和溶解度的影响。该项目有助于加州大学洛杉矶分校的承诺 阿尔茨海默氏病研究中心（ADRC）促进研究将导致鉴定 用于AD和相关疾病的疾病改良疗法。该项目将与项目2互动 评估转基因小鼠中的类似化合物。