Time-lines of neural degeneration in ALS-PDC mouse model

ALS-PDC 小鼠模型神经退行性变的时间线

• 批准号: 7560397
• 负责人: CHRISTOPHER Ariel SHAW
• 金额: $ 20.97万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7560397
• 关键词: Address; Adolescent; Adult; Affect; Age; Astrocytes; Behavioral; Biochemical; Biological Assay; Biological Markers; Cell Death; Cellular Stress; Classification; Cognitive; Complex; Cycad; Data; Dementia; Dependence; Development; Diet; Disease; Disease model; Early treatment; Etiology; Event; Exposure to; Flour; Functional disorder; Future; Generations; Genetic; Genetic Predisposition to Disease; Glucosides; Goals; Hippocampus (Brain); Human; In Vitro; Laboratories; Life; Longevity; Modeling; Motor; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurotoxins; Onset of illness; Outcome; Parkinsonian Disorders; Pathway interactions; Phase; Phosphoric Monoester Hydrolases; Play; Predisposition; Preparation; Process; Prophylactic treatment; Protein Kinase; Proteins; Protocols documentation; Recovery; Recovery of Function; Research; Research Personnel; Role; Seeds; Sensory; Series; Severities; Sitosterol; Sitosterols; Slice; Spinal Cord; Staging; Susceptibility Gene; Testing; Therapeutic Intervention; Time; TimeLine; Toxic Actions; Toxic Environmental Substances; Toxic effect; Toxin; Twin Multiple Birth; Variant; Water; Work; age effect; age related; base; behavior test; behavioral health; design; feeding; human disease; in vivo; indexing; insight; interest; male; mouse model; nervous system disorder; neuropathology; neurotoxicity; novel; postnatal; prevent; programs; prophylactic; relating to nervous system; research study; sterol glucoside; therapeutic target; tissue culture; treatment strategy

ALS parkinsonism-dementia complex (ALS-PDC) is a neurological disease that can present as classical ALS, an Alzeheimer's-like disorder with associated parkinsonism features, or a combination. It is a cluster of age-dependent neurodegenerative disorders, representing the only widely acknowledged such cluster and may offer vital clues to the etiology of related disorders. We have successfully modeled the disease by feeding washed cycad flour to adult mice, which develop behavioral and histopathological deficits resembling ALS-PDC. The ability to model the disease allows us to ask fundamental questions of great potential impact for related disorders: Which environmental toxins and genetic susceptibilities contribute to neurodegeneration? What is the time course of the behavioral and pathological deficits from initial expo- sure until behavioral end state? How does age affect disease development and progression? Finally, based on the above, can we design prophylactic and early treatment strategies to prevent further neurode- generation? Using our model of ALS-PDC, we will address the crucial questions of (1) neurodegeneration time-line and (2) the impact of neurotoxins as a function of age. To probe these questions, adult male CD-1 mice will be fed washed cycad or the isolated putative cycad toxins, variant steryl glucosides. A detailed time-line of behavioral, morphological, and biochemical events will be studied from initial exposure through to an end state for both groups. To further examine crucial events in the neurodegeneration cascade, neural cells will be examined in a tissue culture preparation during and following exposure to steryl glucosides. The proposed age effects study will examine two aspects: cycad neurotoxin-induced behavioral and pathological effects as a function of age over a span of 1 to 18 months. In a second series of experiments, we will determine if an early exposure to cycad toxins can exacerbate a late adult expo- sure. These data will provide therapeutic targets to prevent or halt the progression of neurodegeneration.

ALS帕金森痴呆综合征（ALS-PDC）是一种神经系统疾病，可表现为典型的 ALS，一种具有相关帕金森症特征的阿尔茨海默病样疾病，或其组合。它是一个集群 年龄依赖性神经退行性疾病，代表了唯一被广泛认可的此类集群 并可能为相关疾病的病因学提供重要线索。我们已经成功地模拟了这种疾病， 给成年小鼠喂食洗过的苏铁粉，这些小鼠出现行为和组织病理学缺陷 类似ALS-PDC。对疾病进行建模的能力使我们能够提出重大的基本问题 对相关疾病的潜在影响：哪些环境毒素和遗传易感性会导致 神经退化行为和病理缺陷从最初暴露的时间过程是什么？ 直到行为终结年龄如何影响疾病的发展和进展？最后基于 基于以上所述，我们是否可以设计预防和早期治疗策略，以防止进一步的神经退行性疾病， 一代？使用我们的ALS-PDC模型，我们将解决以下关键问题：（1）神经退行性变 时间线和（2）作为年龄的函数的神经毒素的影响。为了探讨这些问题，成年男性CD-1 将给小鼠喂食洗涤的苏铁或分离的推定苏铁毒素、变体甾醇葡糖苷。详细 将研究从最初接触到 两个组的结束状态。为了进一步研究神经退化级联反应中的关键事件， 在暴露于甾醇期间和之后，将在组织培养制备物中检查神经细胞 葡萄糖苷。拟议的年龄效应研究将考察两个方面：苏铁神经毒素诱导的行为 以及在1至18个月的跨度内作为年龄的函数的病理学效应。在第二系列的 通过实验，我们将确定早期暴露于苏铁毒素是否会加剧晚期成年暴露。 这些数据将为预防或阻止神经退行性疾病的进展提供治疗靶点。