Project 2: Pesticide Mechanisms and PD: Genetic Studies In Flies

项目 2：农药机制和 PD：果蝇基因研究

• 批准号: 8292135
• 负责人: David Evan Krantz
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292135
• 关键词: Address; Affect; Agriculture; Animals; Benomyl; Binding; Biochemical; Biochemical Pathway; Carboxy-Lyases; Cell Culture Techniques; Cell Death; Cell physiology; Cells; Cessation of life; Complement; Data; Databases; Dominant-Negative Mutation; Drosophila genus; Drug Metabolic Detoxication; Environment; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Epidemiology; Exposure to; Future; Generations; Genes; Genetic; Genetic Risk; Goals; Human; Human Genetics; In Vitro; Individual; Investigation; Laboratories; Lesion; Link; Longevity; Microtubules; Modeling; Molecular; Molecular Genetics; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Pesticides; Pharmaceutical Preparations; Principal Investigator; Process; Protein Isoforms; RNA Interference; Reagent; Relative (related person); Risk; Rodent; Rodent Model; Series; System; Testing; Time; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Toxin; Transgenes; Ubiquitin-Activating Enzymes; Ziram; aldehyde dehydrogenases; base; combinatorial; defined contribution; design; dopaminergic neuron; experience; fly; genetic manipulation; in vivo; insight; killings; loss of function mutation; multicatalytic endopeptidase complex; neurotoxic; neurotoxicity; overexpression; pet animal; programs; promoter; research study; tau Proteins; tool

The goal of the UCLA-CGEP is to investigate the hypothesis that the cellular mechanisms of action identified for Putative Environmental Toxicants (PETs) contribute to a significant increase in PD risk; this project (Project 2) willfocus on investigations in Drosophila to Investigate the mechanisms of PET action and their interaction with .genetic lesions in the same cellular pathways. Epidemiological and in vitro data from our. group-have shown that exposure to PETs increases the risk of PD and suggested several potential mechanisms by which PETs may exert toxjc effects in dopaminergic.(DA) neurons: the proteaspme, microtubule function, and detoxification by aldehyde dehydrogenase (ALDH): We also have shown that altered expression of the vesicular mohoamine transporter (VMAT) affects the vulnerability of DA neurons to . neurodegeneration. The three Drosophila labs collaborating on Project 2 have extensive experience using Drosophila genetics to model neurodegenerative disorders and the contribution of environmental insults. Here, we propose to use Drosophila genetics to investigate: 1) which of the known biochemical activities of the PETs contribute to DA cell death, 2) whether PETs and genetic lesions in the same biochemical pathway can combine to increase DA cell death, and 3) how manipulation of VMAT affects the neurotoxicity of the PETs. Drugs and toxins that inhibit these processes have pleiotropic effects, and.we propose to precisely define the contribution of each pathway using molecular genetic mimics to inhibit the proteasome, microtubule function, and aldehyde dehydrogenase. The molecular genetic reagents we will use are either already available or readily made and will include RNA interference to knockdown expression of the ubiquitin activating enzyme (E1), misexpression of two well characterized dominant negative mutations.in 20S proteasome subunits, expression in DA neurons of the longest isoform of human tau, and loss of function mutations in Drosophila ALDH. The results of Project 2 and Project 1 will be used to help develop rodent models in Project 3, and^help determine biochemical pathways to be emphasized in the human genetic studies of Project 4. Fly models for PET exposure also will enable us in future aims to evaluate potential neuroprotective strategies.

UCLA-CGEP的目的是研究细胞作用机制的假设， 推定的环境毒物（PET）导致PD风险显著增加;该项目 （项目2）将集中在果蝇的研究，以研究PET的作用机制及其在果蝇中的作用。 在相同的细胞通路中与遗传病变相互作用。流行病学和体外数据来自我们的。 研究表明，暴露于PET会增加PD的风险，并提出了一些潜在的 PET可能在多巴胺能神经元中发挥毒性作用的机制。(DA)神经元：蛋白酶， 微管功能和醛脱氢酶（ALDH）的解毒作用：我们还表明， 囊泡莫霍胺转运体（VMAT）表达的改变影响DA神经元对... 神经变性在项目2中合作的三个果蝇实验室有着丰富的经验， 果蝇遗传学模拟神经退行性疾病和环境损伤的贡献。 在这里，我们建议使用果蝇遗传学来研究：1）已知的生物化学活性， PETs导致DA细胞死亡，2）PETs和遗传病变是否在同一生化途径中 可以联合收割机增加DA细胞死亡，和3）VMAT的操作如何影响神经毒性的细胞， PETs.抑制这些过程的药物和毒素具有多效性，我们建议精确地 使用分子遗传模拟物来定义每种途径的贡献以抑制蛋白酶体， 微管功能和醛脱氢酶。我们将使用的分子遗传试剂是 并且将包括RNA干扰以敲低泛素的表达 活化酶（E1），两个充分表征的显性阴性的错误表达mutations.in 20 S 蛋白酶体亚基、人tau蛋白最长亚型在DA神经元中的表达和功能丧失 果蝇ALDH的突变项目2和项目1的结果将用于帮助开发啮齿动物 项目3中的模型，并帮助确定在人类遗传学中要强调的生化途径。 研究项目4。PET暴露的飞行模型也将使我们能够在未来的目标，以评估潜在的 神经保护策略