Microglial regulation of Progranulin levels
小胶质细胞对颗粒体蛋白前体水平的调节
基本信息
- 批准号:9917026
- 负责人:
- 金额:$ 62.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskBehavioralBehavioral AssayBiochemicalBiologyBrainCRISPR/Cas technologyCell Culture SystemDNA Sequence AlterationDataDementiaDevelopmentDiseaseEndocytosisFrontotemporal Lobar DegenerationsFutureGeneticGlycoproteinsGoalsGrantHomologous GeneHumanKnockout MiceKnowledgeLeadLinkMediatingMicrogliaMolecularMolecular TargetMusMutationNervous System PhysiologyNeurodegenerative DisordersNeuronal Ceroid-LipofuscinosisOnset of illnessPGRN genePathologicPathologyPathway interactionsPatientsPhenotypePhosphotransferasesPlasmaProtein-Serine-Threonine KinasesProteinsProteomicsRegulationResearchRoleSingle Nucleotide PolymorphismSymptomsTestingTherapeutic InterventionTreatment EfficacyValidationbasebehavioral phenotypingdosageefficacy testinggranulinhuman diseaseimprovedin vivoinduced pluripotent stem cellinsightloss of functionmouse geneticsnemo-like kinasenervous system disorderneuropathologynovel therapeutic interventionoverexpressionpatient subsetspreventreceptortargeted treatmenttherapeutic developmenttrafficking
项目摘要
Genetic mutations in Granulin (GRN) that result in reduced levels of its encoded protein, progranulin (PGRN),
have been implicated in several distinct neurological disorders, depending on the degree of PGRN reduction.
More specifically, haploinsufficiency resulting from heterozygous GRN mutations has been identified to be
causal for a subset of patients with frontotemporal lobar degeneration (FTLD), an adult-onset
neurodegenerative disease. Furthermore, homozygous loss-of-function GRN mutations result in neuronal
ceroid lipofuscinosis (NCL), and single nucleotide variants that decrease plasma and brain PGRN levels are
risk factors for Alzheimer’s Disease (AD). The clear association between reduced levels of PGRN and
neurological disorders highlights the importance of adequate PGRN dosage in normal nervous system
function. The overarching goal of this project is to better understand the precise cellular and molecular
mechanisms that are involved in the regulation of PGRN. In order to reach this goal, we began by identifying
factors that could potentially modulate phenotypes associated with PGRN haploinsufficiency. The preliminary
data presented in this application clearly show that Nemo-like kinase (NLK), an evolutionarily conserved
serine/threonine kinase, is involved in the regulation of PGRN levels and can modulate phenotypes associated
with PGRN reduction in vivo through microglia. To investigate this idea further, we propose the following three
specific aims. In Specific Aim 1, we will determine whether altering Nlk levels specifically in microglia can
modulate FTLD-related phenotypes in vivo using mouse genetics. Specifically, (1) we will first test whether
constitutive loss of Nlk in microglia is able to induce FTLD-related neuropathological and behavioral
phenotypes. (2) Conversely, we will examine if constitutive overexpression of Nlk in microglia can prevent or
ameliorate these same phenotypes. We will focus on neuropathological changes and behavioral deficits that
have been previously ascribed to PGRN reduction in FTLD-PGRN patients and Grn knockout mice. In Specific
Aim 2, we will elucidate the molecular mechanism through which Nlk regulates Pgrn levels in microglia. We will
(1) employ mouse genetics and isogenic human induced pluripotent stem cell-derived microglia to determine
the receptor involved in Nlk-mediated regulation of Pgrn endocytosis and (2) utilize unbiased proteomics
approaches to identify direct molecular targets of Nlk that function in this regulation. In Specific Aim 3, we will
determine whether GRN-associated neuropathology can be suppressed or reversed by increasing Nlk
expression in adulthood. To do this, we will temporally induce the overexpression of Nlk after disease onset
and test the efficacy in ameliorating or reversing pathological and behavioral deficits. We believe that the
knowledge gained from the studies proposed in this application will advance our basic understanding of the
cellular and mechanism underlying PGRN regulation and will suggest new therapeutic interventions aimed at
reducing the burden of FTLD and other neurological disorders associated with PGRN reduction such as AD.
颗粒蛋白(GRN)中存在基因突变,这可能导致其编码的蛋白质PGRN(PGRN)的水平降低。
已经被证实与几种截然不同的神经功能障碍有关,这取决于PGRN减少的程度。
更具体地说,尚未发现由GRN基因杂合性突变导致的单倍体不足。
一组患有额颞叶退行性变(FTLD)的患者的病因分析,这是一例成人发病。
神经退行性疾病。此外,GRN基因突变的纯合子或功能丧失会导致神经元死亡。
类油性脂褐素沉着症(NCL)是一种可降低血浆水平和脑内PGRN水平的单核苷酸突变。
阿尔茨海默氏症的危险因素与阿尔茨海默氏症(AD)的发病密切相关。此外,血清PGRN水平降低与AD之间存在明显的相关性。
神经功能障碍强调了充足的PGRN剂量对正常的神经系统的重要性。
功能。我们这个项目的首要目标是更好地理解最精确的细胞结构和分子生物学。
这些机制也参与了PGRN的监管工作。为了更好地实现这一目标,我们首先确定了这一目标。
这些因素可能会潜在地调节与PGRN单倍体不足相关的表型。
在这份研究申请中提供的数据清楚地表明,Nemo-like蛋白激酶(NLK)是一种进化上保守的基因。
丝氨酸/苏氨酸激酶也参与了PGRN水平的调节,它还可以调节与之相关的表型。
随着PGRN在体内的减少是通过小胶质细胞实现的。为了进一步研究这一想法,我们可以提出以下三个方面的建议。
具体的目标。在具体的目标1中,我们将不确定是否可以改变Nlk的水平,特别是小胶质细胞的水平。
利用小鼠的遗传基因在体内调节FTLD相关的表型。具体地说,我们将首先测试是否有FTLD相关的表型。
小胶质细胞中Nlk基因的结构性丢失可能导致与FTLD相关的神经病理改变和行为改变。
表型。相反,我们将继续研究小胶质细胞中Nlk基因的组成性过度表达是否能有效预防肿瘤的发生。
改善这些相同的表型。我们将继续关注神经病理改变和行为障碍。
此前也有人将其归因于FTLD--PGRN患者的PGRN基因减少和小鼠的GRN基因敲除。
AIM 2,我们将进一步阐明Nlk调节小胶质细胞中PGRN水平的分子调控机制。
(1)利用小鼠遗传基因和人类同源基因诱导的干细胞来源的多能干细胞和小胶质细胞来确定。
受体参与了Nlk介导的PGRN内吞作用的调节过程,并(2)利用了一种公正的蛋白质组学。
我们需要确定在这项法规中发挥作用的Nlk的直接分子药物靶标的方法。在具体的目标3中,我们将继续。
确定是否可以通过增加Nlk来抑制或逆转与GRN相关的神经病理改变。
表达发生在成年期。为了做到这一点,我们希望在疾病发作后暂时诱导Nlk基因的过度表达。
并测试其在改善或逆转病理性精神障碍和行为障碍方面的疗效。我们相信这是最有效的。
从本申请文件中提出的各项研究中获得的知识将有助于促进我们对这一问题的基本理解。
潜在的PGRN的细胞调控机制和机制也将建议针对这些疾病的新的治疗性干预措施。
减轻FTLD和其他神经系统疾病的负担与减少PGRN相关,如AD。
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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Janghoo Lim其他文献
Janghoo Lim的其他文献
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{{ truncateString('Janghoo Lim', 18)}}的其他基金
Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases
ATXN1 在少突胶质细胞和神经退行性疾病中的作用研究
- 批准号:
10762709 - 财政年份:2022
- 资助金额:
$ 62.32万 - 项目类别:
Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases
ATXN1 在少突胶质细胞和神经退行性疾病中的作用研究
- 批准号:
10390899 - 财政年份:2022
- 资助金额:
$ 62.32万 - 项目类别:
Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases
ATXN1 在少突胶质细胞和神经退行性疾病中的作用研究
- 批准号:
10576381 - 财政年份:2022
- 资助金额:
$ 62.32万 - 项目类别:
Investigation of the role of ATXN1 in oligodendroglia and neurodegenerative diseases
ATXN1 在少突胶质细胞和神经退行性疾病中的作用研究
- 批准号:
10632309 - 财政年份:2022
- 资助金额:
$ 62.32万 - 项目类别:
Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases
溶酶体生物合成和神经退行性疾病中新的 NLK 功能的评估
- 批准号:
10458774 - 财政年份:2021
- 资助金额:
$ 62.32万 - 项目类别:
Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases
溶酶体生物合成和神经退行性疾病中新的 NLK 功能的评估
- 批准号:
10616786 - 财政年份:2021
- 资助金额:
$ 62.32万 - 项目类别:
Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases
溶酶体生物合成和神经退行性疾病中新的 NLK 功能的评估
- 批准号:
10317219 - 财政年份:2021
- 资助金额:
$ 62.32万 - 项目类别:
Microglial regulation of Progranulin levels
小胶质细胞对颗粒体蛋白前体水平的调节
- 批准号:
10347312 - 财政年份:2020
- 资助金额:
$ 62.32万 - 项目类别:
Microglial regulation of Progranulin levels
小胶质细胞对颗粒体蛋白前体水平的调节
- 批准号:
10092071 - 财政年份:2020
- 资助金额:
$ 62.32万 - 项目类别:
Microglial regulation of Progranulin levels
小胶质细胞对颗粒体蛋白前体水平的调节
- 批准号:
10536631 - 财政年份:2020
- 资助金额:
$ 62.32万 - 项目类别:
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