Clinical variability and Cell autonomy of Krabbe leukodystrophy
克拉伯脑白质营养不良的临床变异性和细胞自主性
基本信息
- 批准号:8823865
- 负责人:
- 金额:$ 7.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAge-YearsAllelesAntibodiesAstrocytesAttenuatedBehaviorBlood CellsBrainCause of DeathCell FractionationCell NucleusCell membraneCellsCentrifugationCessation of lifeChildClinicalClinical ResearchCoculture TechniquesConditioned Culture MediaCytosolDNADataDemyelinating DiseasesDemyelinationsDeteriorationDiagnosisDiseaseDisease ManagementEnzymesFractionationGene ExpressionGenesGenetic PolymorphismGenotypeGloboid cell leukodystrophyGoalsGolgi ApparatusHigh Pressure Liquid ChromatographyIGF Type 2 ReceptorLysosomesMeasuresMediatingMethodsMicrogliaMitochondriaMusMutationMutation AnalysisNerve DegenerationNeurogliaNeurologicNeuronsOligodendrogliaOrganellesOutcomePathologyPathway interactionsPatientsPhenotypeProcessProcessed GenesPrognostic MarkerProteinsPsychosineReportingRetinal Ganglion CellsReverse Transcriptase Polymerase Chain ReactionSecondary toSymptomsTestingTherapeuticTimeToxic effectTransplantationWestern BlottingWorkaxonal degenerationbasebrain cellcell typecombinatorialdesigndiagnosis designeffective therapygene functionhematopoietic cell transplantationimprovedinfancyinnovationinorganic phosphatekillingsloss of functionmortalitymouse modelmutantmyelin degenerationmyelinationoutcome forecastperoxisomepublic health relevanceresearch studyreuptaketrafficking
项目摘要
DESCRIPTION (provided by applicant): The goal of this proposal is two-fold: 1) to understand why the same mutation in the galactosylceraminidase (Galc) gene results in ample clinical variability among Krabbe leukodystrophy patients, and 2) to understand if brain cells other than oligodendrocytes are directly targeted by GALC deficiency. Answers to these two questions are crucially important for accurate diagnosis and for the design of more effective therapies. This disease is due to autosomal recessive mutations in the lysosomal enzyme GALC, which cause severe demyelination and neurodegeneration. More than 85% of Krabbe patients show infantile-onset, progressive neurologic deterioration and death by two years of age, while others have a late onset, less severe disease. This disease is diagnosed by measuring GALC activity and confirmed by mutation analysis and clinical features. However clinical studies have revealed that the pathogenetic mutation that a patient carries in the GALC gene is not always predictive of outcome, and the reasons for such variability are unclear. Therefore, it is difficult to predict
the disease course accurately. Unfortunately, the only available therapeutic option is hematopoietic cell transplantation (HCT) before symptoms occur, thus prognostic indicators are of utmost importance for disease management. HCT only partially improves survival and attenuates the disease course in the infantile phenotype, presumably by transfer of GALC from donor cells to myelinating cells of the patients. One unanswered question in Krabbe and other demyelinating disease is whether neurodegeneration is only secondary to demyelination, or if neurons or other brain cells are also direct targets of the disease process. I hypothesize that: 1)
In addition to the mutation, cis-polymorphisms also affect the trafficking of GALC to the lysosome which is indispensable for GALC processing and activation, ultimately influencing the phenotype. 2) Any brain cell other than oligodendrocytes can produce toxicity which eventually damages neurons. Two specific aims will test this idea: 1) Identify the effect of the combination of cis-polymorphisms with Galc mutations on GALC trafficking, processing, and activity in the ER, Golgi, and lysosome, 2) Identify the effect of the absence of GALC in each brain cell type on myelination and neurodegeneration. For the first aim, I will test if any of the cis-polymorphisms that have been reported to coexist with certain mutations affects the trafficking of GALC. For the second aim, I will purify each type of brain cell from the twitcher mouse model of Krabbe disease and coculture them in various combinations to elucidate in which cells GALC loss-of-function is important and which cells are the most important target of toxicity in demyelinating neurodegeneration. This approach is innovative because for the first time it considers cell autonomy and the effect of cis- polymorphisms in Krabbe disease. The project will have impact because it will allow us to better understand which factors determine the prognosis of Krabbe patients, and will provide information necessary to design rational and effective therapies.
描述(由申请人提供):该提案的目标是两个方面:1)理解为什么在半乳糖苷酶酶(GALC)基因中相同的突变会导致Krabbe白细胞增强患者之间的临床差异很大,而2)以了解除少突胶质细胞以外的其他脑细胞是否直接靶向了Galc Deficedle。这两个问题的答案对于准确的诊断和设计更有效的疗法至关重要。该疾病是由于溶酶体酶galc中的常染色体隐性突变引起的,导致严重的脱髓鞘和神经变性。超过85%的Krabbe患者表现出婴儿发作,进行性神经系统恶化和死亡的死亡,而其他患者则患有较晚的发病,较严重的疾病。通过测量GALC活性并通过突变分析和临床特征确认该疾病。然而,临床研究表明,患者在GALC基因中携带的致病突变并不总是可以预测结果,而且这种可变性的原因尚不清楚。因此,很难预测
疾病的过程准确。不幸的是,唯一可用的治疗选择是症状发生之前造血细胞移植(HCT),因此预后指标对于疾病管理至关重要。 HCT仅部分改善了生存率,并减弱了婴儿表型中的疾病病程,大概是通过将galc从供体细胞转移到患者的髓细胞细胞。克拉布(Krabbe)和其他脱髓疾病中的一个未解决的问题是神经退行性是仅次于脱髓鞘的,还是神经元或其他脑细胞也是疾病过程的直接靶标。我假设:1)
除突变外,顺式 - 多态性还会影响GALC对溶酶体的运输,这对于GALC加工和激活是必不可少的,最终影响了表型。 2)除少突胶质细胞以外的任何脑细胞都可以产生最终损害神经元的毒性。两个具体的目的将测试这一想法:1)确定顺式 - 造影与GALC突变对ER,GOLGI和溶酶体中GALC贩运,加工和活性的组合的影响,2)确定每种脑细胞类型中缺乏GALC对髓鞘效应和神经神经脱发的影响。为了第一个目的,我将测试是否有任何据报道与某些突变共存的顺式 - 造晶性影响galc的贩运。为了第二个目标,我将从Krabbe疾病的Twitcher小鼠模型中净化每种类型的脑细胞,并以各种组合的形式进行共培养,以阐明细胞GALC功能丧失很重要,哪些细胞是脱髓式神经变性的毒性最重要的目标。这种方法具有创新性,因为它首次考虑细胞自主性以及顺式多态性对Krabbe病的影响。该项目将产生影响,因为它将使我们能够更好地了解哪些因素决定了Krabbe患者的预后,并将提供设计合理有效疗法所需的信息。
项目成果
期刊论文数量(0)
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Daesung Shin其他文献
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{{ truncateString('Daesung Shin', 18)}}的其他基金
Selective galactosylceramidase ablation to study the pathogenesis of Krabbe leukodystrophy
选择性半乳糖神经酰胺酶消融研究克拉伯脑白质营养不良的发病机制
- 批准号:
10316179 - 财政年份:2019
- 资助金额:
$ 7.95万 - 项目类别:
Selective Galactosylceramidase Ablation to Study the Pathogenesis of Krabbe Leukodystrophy
选择性半乳糖神经酰胺酶消融研究克拉伯脑白质营养不良的发病机制
- 批准号:
10531586 - 财政年份:2019
- 资助金额:
$ 7.95万 - 项目类别:
Selective galactosylceramidase ablation to study the pathogenesis of Krabbe leukodystrophy
选择性半乳糖神经酰胺酶消融研究克拉伯脑白质营养不良的发病机制
- 批准号:
10057403 - 财政年份:2019
- 资助金额:
$ 7.95万 - 项目类别:
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