Understanding how DOPA decarboxylase modulates tau in disease

背景：伴有tau蛋白病变的神经退行性疾病包括阿尔茨海默病 慢性创伤性脑病。发生tau蛋白病的两个主要风险因素是 衰老和重复性轻度创伤性脑损伤tau蛋白病的患病率预计会上升， 尤其是退伍军人。然而，对于tau蛋白病没有临床上批准的治疗。 多巴脱羧酶是多巴胺和5-羟色胺合成中的第二种酶， 鉴定为秀丽隐杆线虫模型中tau蛋白病的新遗传调节剂。有趣的是， 其他降低多巴胺和血清素水平的酶的丢失并不影响tau蛋白病 表型，表明多巴胺和5-羟色胺前体的变化，而不是多巴胺和 血清素本身，减少tau蛋白病。 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。 实验：C。elegans tau蛋白病模型和急性切片离体模型 tau蛋白病将用于1）确定介导所见tau蛋白病减少的分子 DOPA脱羧酶的损失2）鉴定介导DOPA脱羧酶减少的信号通路。 3）验证了在C. elegans tau蛋白病模型与哺乳动物tau蛋白病模型。 预期结果：拟议的研究将导致确定新的机制， 调节tau蛋白病和治疗tau蛋白病的新治疗策略。未来的工作将 在tau蛋白病的整个动物模型中评估最有希望的候选物。 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）建立一个实验管道与动物模型，发现新的 2）获得各种必要和必要的知识和经验， 3）建立独立的研究实验室。这些目标将会实现 在导师团队的指导下，透过不同的培训活动，

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.