Understanding how DOPA decarboxylase modulates tau in disease

了解多巴脱羧酶如何调节疾病中的 tau 蛋白

• 批准号: 10438535
• 负责人: Rebecca Liang Kow
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438535
• 关键词: 5-Hydroxytryptophan; Acute; Affect; Aging; Alzheimer' s Disease; Animal Model; Behavioral; Biochemical; Brain; Caenorhabditis elegans; Cause of Death; Clinical; DOPA decarboxylase; Defect; Dementia; Disease; Disease Progression; Dopamine; Enzymes; Evaluation; Frontotemporal Dementia; Functional disorder; Future; Genes; Genetic; Genetic Screening; Goals; Head; Healthcare Systems; Human; Impaired cognition; Knowledge; Laboratory Research; Levodopa; MAPT gene; Mammals; Mediating; Mentorship; Metabolic Pathway; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Pathologic; Pathology; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Prevalence; Proteins; Research; Risk Factors; Role; Serotonin; Signal Pathway; Slice; Tauopathies; Testing; Toxic effect; Training; Training Activity; Transgenic Organisms; Translating; Tryptophan 5-monooxygenase; Tyrosine 3-Monooxygenase; United States; Veterans; Work; career; chronic traumatic encephalopathy; decarboxylase inhibitor; experience; experimental study; human model; interest; metabolomics; mild traumatic brain injury; mouse model; neuron loss; novel; novel therapeutic intervention; novel therapeutics; protein phosphatase inhibitor-2; skills; tau Proteins; tau aggregation; tau phosphorylation; tau-1; therapeutic target

Background: Neurodegenerative diseases with tau pathology (tauopathies) include Alzheimer's disease and chronic traumatic encephalopathy. Two major risk factors for developing tauopathies are aging and repetitive mild traumatic brain injury. The prevalence of tauopathies is expected to rise, especially among Veterans. However, there are no clinically-approved treatments for tauopathies. DOPA decarboxylase, the second enzyme in dopamine and serotonin synthesis, was recently identified as a novel genetic modulator of tauopathy in a Caenorhabditis elegans model. Interestingly, loss of other enzymes that reduced dopamine and serotonin levels did not affect tauopathy phenotypes, indicating that changes in dopamine and serotonin precursors, but not dopamine and serotonin themselves, reduce tauopathy. Hypothesis: Dopamine and serotonin precursors or their metabolites reduce tauopathy by activating specific signaling pathways that modulate tau. Proposed Experiments: The C. elegans tauopathy model and an acute slice ex vivo model of tauopathy will be used to 1) determine the molecules that mediate the reduction of tauopathy seen with loss of DOPA decarboxylase 2) identify the signaling pathways that mediate reduction of tauopathy by loss of DOPA decarboxylase 3) validate mechanisms identified in the C. elegans tauopathy model with a mammalian tauopathy model. Expected Outcomes: The proposed studies will result in the identification of novel mechanisms for regulating tauopathy and new therapeutic strategies for treating tauopathies. Future work will evaluate the most promising candidates in whole animal models of tauopathy. Career and Training Goals: My overall career goal is to discover novel therapeutic strategies against neurodegenerative diseases as head of my own independent research group. The CDA2 goals are therefore 1) to establish an experimental pipeline with animal models for discovery of novel therapeutics against tauopathies 2) to gain knowledge and experience in various necessary and relevant skills 3) to establish an independent research laboratory. These goals will be achieved through various training activities under the guidance from my mentorship team.

背景：tau病理的神经退行性疾病包括阿尔茨海默氏症 疾病和慢性创伤性脑病。患肥胖症的两个主要风险因素是 衰老和重复性轻度创伤性脑损伤。紧张症的患病率预计会上升， 尤其是在退伍军人中。然而，目前还没有临床批准的治疗肥胖症的方法。 多巴脱羧酶是多巴胺和5-羟色胺合成的第二种酶，是最近发现的。 在秀丽隐杆线虫模型中被确定为一种新的变态反应的遗传调节因子。有趣的是， 降低多巴胺和5-羟色胺水平的其他酶的丢失不会影响直立性病变 表型，表明多巴胺和5-羟色胺前体的变化，但不是多巴胺和 5-羟色胺本身，减少变态反应。 假设：多巴胺和5-羟色胺前体或其代谢物通过激活 调节tau蛋白的特定信号通路。 建议的实验：线虫对位病模型和急性切片体外模型 紧张症将被用来1)确定调节紧张症减少的分子 随着DOPA脱羧酶的丢失2)确定介导细胞减少的信号通路 通过失去DOPA脱羧酶引起的转位性病变3)验证线虫中发现的机制 共济失调模型与哺乳动物共济失调模型。 预期结果：拟议的研究将导致确定新的机制 调节脊椎病和治疗脊椎病的新治疗策略。未来的工作将是 评估整体动物模型中最有希望的直肠反复症候选动物。 职业和培训目标：我的总体职业目标是发现新的治疗策略 作为我自己的独立研究小组的负责人，对抗神经退行性疾病。CDA2 因此，目标是1)建立一个实验管道，用动物模型发现新的 治疗肌萎缩侧索硬化症2)获得各种必要和 相关技能3)建立独立的研究实验室。这些目标将会实现 在我的导师团队的指导下，通过各种培训活动。