The Role of Sensory Receptors in Angelman Syndrome
感觉感受器在天使综合症中的作用
基本信息
- 批准号:10630683
- 负责人:
- 金额:$ 51.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsActin-Binding ProteinActinsAction PotentialsAfferent NeuronsAgonistAllelesAngelman SyndromeAnimalsAtomic Force MicroscopyBehaviorBehavioralBiochemicalBiochemistryBiophysicsBrainBypassCell membraneCellsChemicalsCytoskeletonDataDietDiseaseElectrophysiology (science)EndowmentEquilibriumEvaluationF-ActinGaitGait abnormalityGenetic ModelsGoalsGolgi Tendon OrgansHumanHuman Cell LineHuman GeneticsIndividualIntellectual functioning disabilityInterventionIon ChannelKnockout MiceKnowledgeLengthLigaseLimb structureLinoleic AcidsLipidsMeasuresMechanicsMediatingMembraneMicrofilamentsMissionMolecularMovementMusMuscle SpindlesMutationNeuronsPiezo 2 ion channelPolyunsaturated Fatty AcidsPositioning AttributePosturePropertyProprioceptionProteinsPublic HealthRepressionResearchRoleSafflower OilSeizuresSensorySensory AtaxiasSensory ReceptorsSpecificitySpectrinSpinal GangliaSupplementationTestingUBE3A geneUnited States National Institutes of HealthUnsteady GaitWalkingWheelchairsWorkcofilinconditional knockoutfeedingimprovedin vivoknock-downlipidomicsloss of functionloss of function mutationmotor impairmentmouse modelneurogeneticsoptogeneticspaternal imprintstem cellsubiquitin-protein ligasewalker
项目摘要
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behavior.
AS results from a loss of expression of the E3 ubiquitin-protein ligase (UBE3A) from the maternal allele. The
UBE3A gene is paternally imprinted (i.e., repressed) in most neurons of humans and mice. Deletion, mutation,
or loss of expression of the maternal allele results in AS. Individuals with AS display impaired motor coordination
(e.g., inability to reach objects), gait deficits (i.e., instability while walking), and seizures. There are no
interventions for ameliorating gait deficits. A critical barrier for treating this condition is that the molecular
mechanisms that give rise to gait deficits in AS are unknown. Proprioception confers the ability to sense
movement, balance, and limb position. The mechanosensitive ion channel PIEZO2 is expressed in sensory
neurons innervating muscle spindles and Golgi tendon organs, where it mediates proprioception, gait, and
balance. Mice and humans lacking PIEZO2 expression have an unsteady gait, increased stride-to-stride
variability in step length, and postural deficits. The rationale for these studies relies on the evidence from human
genetics and mouse models suggesting that individuals with AS or PIEZO2 loss-of-function mutations may share
mechanosensation deficits. Our hypothesis is that AS-associated gait deficits originate from reduced PIEZO2
function in sensory neurons. Our preliminary data support our hypothesis because it shows that PIEZO2 currents
are reduced in Ube3a-deficient mouse neurons, human cells with UBE3A knock-down, and stem cell-derived
neurons from individuals with AS. There are no available agonists to increase PIEZO2 activity. Molecules that
enhance PIEZO2 function could bypass the mechanical deficits associated with the loss of UBE3A expression.
We determined that a safflower oil diet, enriched in linoleic acid (LA), increases PIEZO2 currents and mechanical
excitability, as well as improves gait in AS mice. Likewise, LA supplementation enhances PIEZO2 function in
stem cell-derived neurons from individuals with AS. Our overall objective is to determine the mechanisms by
which loss of UBE3A expression decreases PIEZO2 currents (and/or expression) and LA recovers channel
function. To this end, we will carry out electrophysiological, biochemical, biophysical, and behavioral analyses to
provide a detailed understanding of the contribution of UBE3A and PIEZO2 to AS. We will pursue three Specific
Aims: 1) Determine the mechanism whereby loss of UBE3A expression decreases PIEZO2 currents, 2)
Determine the mechanism by which LA increases PIEZO2 activity, and 3) Test the hypothesis that LA
ameliorates gait deficits in AS through PIEZO2. The proposed research is significant because it is expected to
provide a detailed understanding of the molecular mechanisms that accounts for diminished PIEZO2 currents in
AS and the role of LA-enriched membranes in increasing PIEZO2 function.
Angelman综合征(AS)是一种以智力残疾和非典型行为为特征的神经遗传性疾病。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Julio F Cordero-Morales其他文献
Julio F Cordero-Morales的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Julio F Cordero-Morales', 18)}}的其他基金
Sensory Ion Channel Modulation by Bioactive Lipids
生物活性脂质对感觉离子通道的调节
- 批准号:
10622095 - 财政年份:2023
- 资助金额:
$ 51.21万 - 项目类别:
Sensory Ion Channel Modulation by Bioactive Lipids
生物活性脂质对感觉离子通道的调节
- 批准号:
10978347 - 财政年份:2023
- 资助金额:
$ 51.21万 - 项目类别:
Spectroscopic analyses of TRPV1 during gating
门控过程中 TRPV1 的光谱分析
- 批准号:
10039442 - 财政年份:2020
- 资助金额:
$ 51.21万 - 项目类别:
The Role of Bioactive Lipids in Transient Receptor Potential Channels Gating
生物活性脂质在瞬时受体电位通道门控中的作用
- 批准号:
10327700 - 财政年份:2018
- 资助金额:
$ 51.21万 - 项目类别:
The Role of Bioactive Lipids in Transient Receptor Potential Channels Gating
生物活性脂质在瞬时受体电位通道门控中的作用
- 批准号:
10080740 - 财政年份:2018
- 资助金额:
$ 51.21万 - 项目类别:
相似海外基金
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
- 批准号:
6316669 - 财政年份:2000
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
- 批准号:
6338828 - 财政年份:2000
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
- 批准号:
6107703 - 财政年份:1999
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
- 批准号:
6271817 - 财政年份:1998
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
- 批准号:
6240599 - 财政年份:1997
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS & ACTIN-BINDING PROTEIN
肌动蛋白的结构/相互作用
- 批准号:
3287441 - 财政年份:1985
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS & ACTIN-BINDING PROTEIN
肌动蛋白的结构/相互作用
- 批准号:
3287442 - 财政年份:1985
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS & ACTIN-BINDING PROTEIN
肌动蛋白的结构/相互作用
- 批准号:
3287445 - 财政年份:1985
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS & ACTIN-BINDING PROTEIN
肌动蛋白的结构/相互作用
- 批准号:
3287439 - 财政年份:1985
- 资助金额:
$ 51.21万 - 项目类别:
STRUCTURE/INTERACTIONS OF ACTINS & ACTIN-BINDING PROTEIN
肌动蛋白的结构/相互作用
- 批准号:
3287443 - 财政年份:1985
- 资助金额:
$ 51.21万 - 项目类别:














{{item.name}}会员




