Homeostatic control of the NMDA receptor co-agonist D-serine by SLC1A4
SLC1A4 对 NMDA 受体共激动剂 D-丝氨酸的稳态控制
基本信息
- 批准号:10366058
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-17 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAffectAgonistAmino Acid TransporterAmino AcidsAntibodiesBehaviorBindingBiological AssayBrainBrain DiseasesCellsCognitiveCognitive deficitsDataDevelopmentDiseaseDisease modelElectrophysiology (science)FamilyFamily memberGenesGeneticGlutamate TransporterGlutamatesGlycineHomeostasisHumanHuman EngineeringHydroxyprolineImpaired cognitionLearningLinkMCHR1 geneMeasurementMeasuresMediatingMemoryMolecularMusMutationN-Methyl-D-Aspartate ReceptorsNR1 geneNeuroanatomyNeurodevelopmental DeficitNeurodevelopmental ImpairmentNeutral Amino Acid Transport SystemsOocytesPatternPharmacologyPhysiologicalPhysiologyPlayProcessPropertyRadiolabeledReceptor SignalingReporterRoleRouteSchizophreniaSerineSignal TransductionSiteSliceSocial BehaviorSodiumSpecificityStructureSynapsesSynaptic TransmissionSynaptic plasticityTestingTimeTransgenic MiceXenopus laevisdiphenyldisease-causing mutationextracellularhuman diseaseinhibitormouse modelnervous system disorderneurodevelopmentnovelparalogous genepharmacophoreradiotracerreceptorreceptor functionreuptakesolutetheoriesuptakevoltage clamp
项目摘要
NMDA receptors (NMDARs) participate in processes ranging from neural development to
learning and memory. Disorders of NMDAR signaling are linked to several neurological
diseases. Accumulating evidence suggests that the endogenous co-agonist D-serine plays a
prominent role in activation of synaptic NMDARs in cortex. However, there are significant gaps
in our understanding of the physiological mechanisms involved in D-serine homeostasis in brain
and their potential impact on NMDAR signaling. Our preliminary data suggest that SLC1A4, a
neutral amino acid transporter paralog within the SLC1 solute carrier family that includes
glutamate transporters, unexpectedly mediates transmembrane flux of D-serine. We will test the
hypotheses that SLC1A4 is in fact the major route of sodium-dependent D-serine uptake in
brain and that selective SLC1A4 inhibitors developed from a hydroxyproline pharmacophore can
alter D-serine homeostasis and thereby modulate NMDAR function and synaptic plasticity. We
will also characterize the structure and function of a recently identified mutation in the human
gene encoding SLC1A4 that is linked to neurodevelopmental and cognitive deficits, and we will
create and study a transgenic mouse model of this human disease.
NMDA受体(NMDAR)参与从神经发育到
学习和记忆。NMDAR信号转导障碍与几种神经系统相关
疾病。越来越多的证据表明,内源性共同激动剂D-丝氨酸在
在皮质突触NMDARs的激活中起着重要作用。然而,存在着显著的差距。
在我们对大脑D-丝氨酸稳态参与的生理机制的理解中
以及它们对NMDAR信号的潜在影响。我们的初步数据表明,SLC1A4,a
SLC1溶质载体家族中的中性氨基酸转运体Paralog,包括
谷氨酸转运体,出人意料地调节D-丝氨酸的跨膜通量。我们将测试
假设SLC1A4实际上是钠依赖的D-丝氨酸摄取的主要途径
大脑和从羟脯氨酸药效团开发的选择性SLC1A4抑制剂可以
改变D-丝氨酸稳态,从而调节NMDAR功能和突触可塑性。我们
也将表征最近发现的人类突变的结构和功能
编码SLC1A4的基因与神经发育和认知缺陷有关,我们将
创建并研究这种人类疾病的转基因小鼠模型。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Generation and characterization of a knock-in mouse model for Spastic Tetraplegia, Thin Corpus Callosum, and Progressive Microcephaly (SPATCCM).
痉挛性四肢瘫痪、薄胼胝体和进行性小头畸形 (SPATCCM) 敲入小鼠模型的生成和表征。
- DOI:10.21203/rs.3.rs-2839029/v1
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Ratz,MeganL;Leary,Greg;Grindeland,Andrea;Silvius,Derek;Guter,Joseph;Kavanaugh,MichaelP;Gunn,TeresaM
- 通讯作者:Gunn,TeresaM
{{
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 }}
Teresa M Gunn其他文献
Teresa M Gunn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('Teresa M Gunn', 18)}}的其他基金
A protein traffic control system that regulates left-right patterning and heart development
调节左右模式和心脏发育的蛋白质交通控制系统
- 批准号:
10181808 - 财政年份:2021
- 资助金额:
$ 40.5万 - 项目类别:
Parkin and MGRN1: common roles in mitochondria and neurodegeneration?
Parkin 和 MGRN1:在线粒体和神经退行性疾病中的共同作用?
- 批准号:
7878499 - 财政年份:2010
- 资助金额:
$ 40.5万 - 项目类别:
Parkin and MGRN1: common roles in mitochondria and neurodegeneration?
Parkin 和 MGRN1:在线粒体和神经退行性疾病中的共同作用?
- 批准号:
8039080 - 财政年份:2010
- 资助金额:
$ 40.5万 - 项目类别:
Functional analysis of Attractin-Mahogunin signaling
Attractin-Mahogunin 信号传导的功能分析
- 批准号:
7249350 - 财政年份:2003
- 资助金额:
$ 40.5万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 40.5万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 40.5万 - 项目类别:
Operating Grants