O-glycosylation mechanisms of neurological deficits in congenital disorders of glycosylation
先天性糖基化障碍神经功能缺损的O-糖基化机制
基本信息
- 批准号:10040788
- 负责人:
- 金额:$ 18.08万
- 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:2020-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAstrocytesBiologyBrainCareer MobilityCell LineCellsCellular MorphologyComplexCongenital disorders of glycosylationConstitutionalDevelopmentDevelopment PlansDevelopmental Delay DisordersDiseaseEpilepsyEventExhibitsFamily memberFoundationsFunctional disorderFundingFutureGeneticGenetic DiseasesGlycobiologyGlycoproteinsGoalsHumanIndividualInternationalInvestigationKnockout MiceLoxP-flanked alleleMass Spectrum AnalysisMediatingMentorsMicrocephalyModelingMolecularMorphologyMucinsMusMutationNervous System PhysiologyNervous system structureNeurobiologyNeurologicNeurologic DeficitNeurologic DysfunctionsNeuronsNeurosciencesPathway interactionsPatientsPhenotypePhysiciansPost-Translational Protein ProcessingProcessProtein IsoformsProteinsRare DiseasesResearchRoleScientistSignal TransductionSiteSymptomsTechniquesTherapeuticTrainingbehavioral phenotypingcareer developmentcell motilitycell typecomparativeconditional knockoutdesignglycoproteomicsglycosylationglycosyltransferasein vitro Assayinsightknowledge basemolecular phenotypemotor deficitmouse modelnervous system disorderneurotransmitter releaseprogramsprotein functionrare genetic disorderrelating to nervous systemsensory integrationskillstool
项目摘要
PROJECT SUMMARY/ABSTRACT
Glycosylation is an essential, post-translational modification with complex and poorly understood roles in
protein function. My long-term objective is to elucidate the neurobiological functions of glycosylation, including
identifying the roles of critical glycosylation sites in neuronal protein function. The importance of glycosylation
is emphasized by the congenital disorders of glycosylation (CDG), a group of genetic disorders that disrupt
cellular glycosylation machinery. Affected patients exhibit severe neurological deficits. The genetic basis of
CDG provides an opportunity to identify the neurobiological functions of glycosylation using mouse models and
glycoproteomics. Understanding glycosylation in the nervous system will elucidate the pathophysiology of
CDGs and other neurological diseases, enable therapeutic advances targeting glycosylation pathways, and
inform normal function of glycosylation.
GALNT2-CDG is a new CDG type caused by biallelic mutations in GALNT2, which encodes a critical
glycosyltransferase initiating the first step in mucin-type O-glycosylation. GALNT2-CDG patients suffer from
epilepsy and global developmental delay. Galnt2 constitutional knock-out mice recapitulate many of the patient
neurological deficits. My central hypothesis is that site-specific loss of O-glycosylation on neural proteins
contributes to neurological dysfunction. The specific objective of this project is to identify the cause of
neurological dysfunction in GALNT2-CDG. This will be achieved by determining cellular origins of Galnt2
deficiency-mediated neurological deficits using Cre-mediated deletion of Galnt2 in neural cells and by
identifying disrupted O-glycosylation in these cells using glycoproteomics.
This proposed five-year career development plan focuses on achieving four objectives: develop research skills
in mouse models and glycoproteomics, increase my knowledgebase in neuroscience and glycobiology,
establish a body of work focusing on the role of glycosylation in the context of neurobiology, and obtain the
necessary skills to transition to independence. Mentoring will be provided by Dr. Zhaolan Zhou, a recognized
leader in the development and investigation of mouse models of genetic disorders that affect brain
development and function, and Dr. Benjamin Garcia, a recognized expert in developing quantitative mass
spectrometry techniques to interrogate post-translational modifications.
The skill set developed through these investigations and career development plan will make me uniquely
poised to uncover glycosylation-mediated mechanisms of CDG and other neurological diseases, as well as to
elucidate the critical roles of glycosylation in human neurological function. These studies will generate new
tools and a foundation to establish a long-term research program to investigate the pathophysiology of various
glycosylation-related disorders in the nervous system and prepare me to become an independent R01-funded
physician scientist.
项目总结/摘要
糖基化是一种重要的翻译后修饰,其作用复杂且知之甚少,
蛋白质功能我的长期目标是阐明糖基化的神经生物学功能,包括
确定神经元蛋白质功能中关键糖基化位点的作用。糖基化的重要性
先天性糖基化障碍(CDG)是一组遗传性疾病,
细胞糖基化机制。受影响的患者表现出严重的神经功能缺损。的遗传基础
CDG提供了使用小鼠模型鉴定糖基化的神经生物学功能的机会,
糖蛋白质组学了解神经系统中的糖基化将阐明
CDG和其他神经系统疾病使靶向糖基化途径的治疗进展成为可能,
告知糖基化的正常功能。
GALNT 2-CDG是由GALNT 2中的双等位基因突变引起的一种新的CDG类型,其编码关键的
糖基转移酶启动粘蛋白型O-糖基化的第一步。GALNT 2-CDG患者患有
癫痫和全面发育迟缓。Galnt 2基因敲除小鼠重现了许多患者
神经缺陷我的中心假设是神经蛋白上的O-糖基化位点特异性缺失
会导致神经功能障碍本项目的具体目标是查明
GALNT 2-CDG的神经功能障碍。这将通过确定Galnt 2的细胞起源来实现
在神经细胞中使用Cre介导的Galnt 2缺失和通过
使用糖蛋白质组学鉴定这些细胞中被破坏的O-糖基化。
这一拟议的五年职业发展计划侧重于实现四个目标:发展研究技能
在小鼠模型和糖蛋白组学方面,增加我在神经科学和糖生物学方面的知识基础,
建立一个工作机构,重点是糖基化在神经生物学背景下的作用,并获得
需要具备向独立过渡的能力。导师将由周兆兰博士提供,
在开发和研究影响大脑的遗传疾病的小鼠模型方面处于领先地位
发展和功能,本杰明加西亚博士,在发展定量质量公认的专家,
光谱技术来询问翻译后修饰。
通过这些调查和职业发展计划开发的技能将使我成为独一无二的
准备揭示糖基化介导的CDG和其他神经系统疾病的机制,以及
阐明糖基化在人类神经功能中的关键作用。这些研究将产生新的
工具和基础,以建立一个长期的研究计划,以调查各种病理生理学
糖基化相关的神经系统疾病,并准备我成为一个独立的R 01资助的
医学科学家
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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Andrew Charles Edmondson其他文献
Andrew Charles Edmondson的其他文献
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{{ truncateString('Andrew Charles Edmondson', 18)}}的其他基金
Identifying understudied protein-related glycoproteome disruption in Congenital Disorders of Glycosylation
识别先天性糖基化障碍中尚未研究的蛋白质相关糖蛋白组破坏
- 批准号:
10725869 - 财政年份:2023
- 资助金额:
$ 18.08万 - 项目类别:
O-glycosylation mechanisms of neurological deficits in congenital disorders of glycosylation
先天性糖基化障碍神经功能缺损的O-糖基化机制
- 批准号:
10250486 - 财政年份:2020
- 资助金额:
$ 18.08万 - 项目类别:
O-glycosylation mechanisms of neurological deficits in congenital disorders of glycosylation
先天性糖基化障碍神经功能缺损的O-糖基化机制
- 批准号:
10689139 - 财政年份:2020
- 资助金额:
$ 18.08万 - 项目类别:
Endothelial lipase: a modulator of HDL metabolism and atherosclerosis in humans
内皮脂肪酶:人类 HDL 代谢和动脉粥样硬化的调节剂
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Endothelial lipase: a modulator of HDL metabolism and atherosclerosis in humans
内皮脂肪酶:人类 HDL 代谢和动脉粥样硬化的调节剂
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7545618 - 财政年份:2008
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$ 18.08万 - 项目类别:
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