Endoplasmic Reticulum Stress in Neurodegeneration
神经变性中的内质网应激
基本信息
- 批准号:9911998
- 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:2017
- 资助国家:美国
- 起止时间:2017-02-01 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAgingAlzheimer&aposs DiseaseAmericanAmino Acid SubstitutionAmino AcidsAnimal ModelAnimalsBiochemicalBiological AssayBrainCell DeathCell SurvivalCell physiologyCellsDataDevelopmentDiseaseDisease modelElderlyEndoplasmic ReticulumEukaryotic Initiation FactorsEventFibroblastsFunctional disorderGenesGeneticGenetic EnhancementHaplotypesHumanImpairmentIntegral Membrane ProteinKineticsKorean WarLate Onset Alzheimer DiseaseMeasuresMessenger RNAMissionModelingMolecularMolecular GeneticsMorbidity - disease rateMusNerve DegenerationNervous system structureNeurodegenerative DisordersNeurofibrillary TanglesNeuronsOralPERK kinasePathogenesisPathologicPathologyPatient CarePatientsPharmaceutical PreparationsPharmacologyPhosphorylationPhosphotransferasesPluripotent Stem CellsPopulationPredispositionProgressive Supranuclear PalsyPropertyProtein KinaseProteinsRecombinantsResearchRibosomesRiskRoleSignal TransductionSignal Transduction PathwaySkinTauopathiesTestingTransgenic MiceTranslationsVariantVeteransVietnam Conflictbasebehavioral studydimereffective therapyendoplasmic reticulum stressexperimental studygenetic risk factorgenetic variantgenome wide association studygenome-wide analysishigh riskhistological studieshuman diseasein vitro activityin vivoinsightmisfolded proteinmolecular pathologymortalitymouse modelmutantneuron lossneuronal survivalneuropathologynovelnovel therapeuticspreservationpreventprotein foldingprotein misfoldingreconstitutionresponserisk variantsmall moleculestem cellstau Proteins
项目摘要
Neurodegenerative diseases are a significant cause of morbidity and mortality in elderly Veterans. No cures
exist for neurodegenerative diseases, because the cellular, molecular, and genetic mechanisms that cause
neurons to die with age are poorly understood. Our long-term objective is to decipher the mechanisms
required for neuronal function and survival and to identify how dysfunction of these mechanisms contribute to
progressive age-associated neurodegenerative diseases. Comprehensive genome wide studies of patients
with late-onset Alzheimer's disease and Progressive Supranuclear Palsy recently identified the eukaryotic
translation initiation factor 2α kinase 3/PKR-like endoplasmic reticulum kinase (EIF2AK3/PERK) gene as a
genetic risk factor for neurodegeneration. EIF2AK3/PERK encodes an endoplasmic reticulum transmembrane
protein kinase that is essential for cells to survive pathologic and environmental conditions that cause
misfolded proteins and endoplasmic reticulum stress. In response to misfolded proteins and ER stress,
EIF2AK3/PERK dimerizes to activate its kinase domain. Multiple EIF2AK3/PERK haplotypes with various
amino acid substitutions are found in the human population. The function of EIF2AK3/PERK in neurons and
the mechanism by which some EIF2AK3/PERK haplotypes cause neurodegeneration are unknown. We
recently discovered that EIF2AK3/PERK haplotypes associated with neurodegeneration have significantly
reduced kinase activity compared to protective haplotypes. We also found that neurons generated from skin
fibroblasts of patients with high-risk EIF2AK3/PERK haplotypes showed impaired EIF2AK3/PERK signaling in
response to ER stress. Last, we found that EIF2AK3/PERK signaling is robustly activated in a mouse model of
tauopathy neurodegeneration. Based on these preliminary findings, our central hypothesis is that
EIF2AK3/PERK is activated during neurodegeneration to preserve neuronal cell function and viability, and loss
of EIF2AK3/PERK function leads to increased protein misfolding and increased ER stress that ultimately cause
neuronal cell death and neurodegeneration. We propose cellular, molecular, and genetic experiments to test
this hypothesis and determine the function of EIF2AK3/PERK in neurodegeneration. First, we will characterize
the biochemical and enzymatic activities of high-risk and low-risk human EIF2AK3/PERK associated with
neurodegeneration. We will perform biochemical studies of recombinant EIF2AK3/PERK proteins to analyze
the functional consequences of amino acid alterations associated with human haplotype variants. Second, we
will test if modulation of EIF2AK3/PERK signaling prevents disease in the PS19 transgenic mouse model of
neurodegeneration. We will cross PS19 mice with genetically modified mice that increase EIF2AK3/PERK
signaling. We will treat PS19 mice with orally available drugs that increase or inhibit EIF2AK3/PERK signaling.
We will perform molecular, histologic, and behavioral studies to examine how EIF2AK3/PERK modulation
affects neuropathology and neurodegeneration in this animal model. Last, we will evaluate EIF2AK3/PERK
signal transduction in stem cell-derived neurons generated from patients with high-risk and low-risk
EIF2AK3/PERK haplotypes. We will determine how genetic variants of EIF2AK3/PERK affect neuronal tau
protein folding and neuronal susceptibility to ER stress-induced cell death. In parallel, we will test novel
pharmacologic modulators of EIF2AK3/PERK signaling to see if we can prevent neuronal cell death when
PERK is artificially activated. In summary, EIF2AK3/PERK variants are important genetic risk factors for
developing neurodegeneration but their function and mechanisms are unknown and treatments are lacking.
These studies are significant because they will reveal the role of EIF2AK3/PERK in neurons and why
EIF2AK3/PERK variants in people can increase risk for developing neurodegeneration. Our studies will
positively benefit the mission of the VA by identifying potential treatments to prevent neurodegeneration in
Veterans and patients carrying the high-risk alleles.
神经退行性疾病是老年退伍军人发病和死亡的一个重要原因,目前尚无治愈方法。
神经退行性疾病存在,因为导致神经退行性疾病的细胞、分子和遗传机制
我们对神经元随着年龄的增长而死亡的机制知之甚少。
神经功能和生存所需的,并确定这些机制的功能障碍如何导致
对患者的进行性年龄相关神经退行性疾病的全面基因组研究。
最近发现了晚发性阿尔茨海默病和进行性核上性麻痹的真核生物
翻译起始因子 2α 激酶 3/PKR 样内质网激酶 (EIF2AK3/PERK) 基因作为
EIF2AK3/PERK 编码内质网跨膜遗传风险因素。
蛋白激酶对于细胞在病理和环境条件下生存至关重要
错误折叠的蛋白质和内质网应激响应错误折叠的蛋白质和内质网应激。
EIF2AK3/PERK 二聚化以激活其激酶结构域和各种不同的 EIF2AK3/PERK 单倍型。
在人类中发现了 EIF2AK3/PERK 在神经元和中的功能。
一些 EIF2AK3/PERK 单倍型导致神经变性的机制尚不清楚。
最近发现与神经退行性变相关的 EIF2AK3/PERK 单倍型显着
与保护性单倍型相比,激酶活性降低我们还发现从皮肤产生的神经元。
具有高危 EIF2AK3/PERK 单倍型的患者的成纤维细胞显示,EIF2AK3/PERK 信号传导受损
最后,我们发现 EIF2AK3/PERK 信号在小鼠模型中被强烈激活。
基于这些初步发现,我们的中心假设是:
EIF2AK3/PERK 在神经退行性变期间被激活,以保持神经细胞功能和活力以及损失
EIF2AK3/PERK 功能的丧失导致蛋白质错误折叠增加和 ER 应激增加,最终导致
我们建议通过细胞、分子和基因实验来测试神经细胞死亡和神经变性。
首先,我们将描述这一假设并确定 EIF2AK3/PERK 在神经变性中的功能。
高风险和低风险人类 EIF2AK3/PERK 的生化和酶活性与
我们将对重组 EIF2AK3/PERK 蛋白进行生化研究以进行分析。
与人类单倍型变异相关的氨基酸改变的功能后果 其次,我们。
将测试 EIF2AK3/PERK 信号传导的调节是否可以预防 PS19 转基因小鼠模型中的疾病
我们将 PS19 小鼠与增加 EIF2AK3/PERK 的转基因小鼠杂交。
我们将用增强或抑制 EIF2AK3/PERK 信号传导的口服药物治疗 PS19 小鼠。
我们将进行分子、组织学和行为研究,以检查 EIF2AK3/PERK 调节如何
最后,我们将评估 EIF2AK3/PERK。
高风险和低风险患者产生的干细胞衍生神经元的信号转导
我们将确定 EIF2AK3/PERK 的遗传变异如何影响神经元 tau。
与此同时,我们将测试新的蛋白质折叠和神经对内质网应激诱导的细胞死亡的敏感性。
EIF2AK3/PERK 信号传导的药理调节剂,看看我们是否可以预防神经元细胞死亡
PERK 是人为激活的。综上所述,EIF2AK3/PERK 变异是重要的遗传危险因素。
发展为神经退行性疾病,但其功能和机制尚不清楚,且缺乏治疗方法。
这些研究意义重大,因为它们将揭示 EIF2AK3/PERK 在神经元中的作用及其原因
人类的 EIF2AK3/PERK 变异会增加发生神经退行性变的风险。
通过确定预防神经退行性变的潜在治疗方法,积极有利于 VA 的使命
携带高风险等位基因的退伍军人和患者。
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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JONATHAN LIN其他文献
JONATHAN LIN的其他文献
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