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
基本信息
- 批准号:10084236
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:5-HydroxytryptophanAcuteAffectAgingAlzheimer&aposs DiseaseAnimal ModelBehavioralBiochemicalBrainCaenorhabditis elegansCause of DeathClinicalDOPA decarboxylaseDefectDementiaDiseaseDisease ProgressionDopamineEnzymesEvaluationFrontotemporal DementiaFunctional disorderFutureGenesGeneticGenetic ScreeningGoalsHeadHealthcare SystemsHumanImpaired cognitionKnowledgeLaboratory ResearchLevodopaMAPT geneMammalsMediatingMentorshipMetabolic PathwayModelingMusNerve DegenerationNeurodegenerative DisordersNeuronsOutcomePathologicPathologyPharmaceutical PreparationsPhenotypePhosphoric Monoester HydrolasesPhosphotransferasesPrevalenceProteinsResearchRisk FactorsRoleSerotoninSignal PathwaySliceTauopathiesTestingToxic effectTrainingTraining ActivityTransgenic OrganismsTranslatingTryptophan 5-monooxygenaseTyrosine 3-MonooxygenaseUnited StatesVeteransWorkcareerchronic traumatic encephalopathydecarboxylase inhibitorexperienceexperimental studyhuman modelinterestmetabolomicsmild traumatic brain injurymouse modelneuron lossnovelnovel therapeutic interventionnovel therapeuticsprotein phosphatase inhibitor-2skillstau Proteinstau aggregationtau phosphorylationtau-1therapeutic target
项目摘要
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: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。
拟议的实验: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
对抗神经退行性疾病,作为我自己独立研究小组的负责人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,
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rebecca Liang Kow其他文献
Rebecca Liang Kow的其他文献
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{{ truncateString('Rebecca Liang Kow', 18)}}的其他基金
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:
10552609 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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 - 财政年份:2019
- 资助金额:
-- - 项目类别:
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