Activation and Regulation of the Synaptic Receptor BAI1
突触受体 BAI1 的激活和调节
基本信息
- 批准号:9900070
- 负责人:
- 金额:$ 23.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:ANXA5 geneAffectAmino Acid SubstitutionAmino AcidsAngiogenesis InhibitorsApoptosisApoptoticBAI1 geneBindingBiologyBrainC2 DomainCell membraneCellsChemosensitizationCouplingDendritic SpinesDevelopmentDiseaseEvolutionExcisionExhibitsExtracellular DomainFamilyG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGenesGeneticGenetic studyGoalsHeritabilityHippocampus (Brain)HumanInstitutesKnock-outKnockout MiceLigandsLightLinkMediatingMental disordersMissense MutationMusMutateMutationNeuraxisNeuronsOther GeneticsPathologyPathway interactionsPhosphatidylserinesPhysiologicalPopulationProteinsReceptor SignalingRegulationReportingRiskRodentRoleSchizophreniaSignal PathwaySignal TransductionStimulusStructureSurfaceSynapsesSynaptic ReceptorsSynaptic plasticityTestingTransfectionTwin StudiesUniversitiesWorkdensityexomeextracellulargenetic analysisinsightmembermutantnovelphospholipid scramblaserare variantreceptorsmall molecule therapeuticstrafficking
项目摘要
Project Summary
Schizophrenia is a devastating psychiatric disorder that affects ~1% of the USA population. Over the past
few decades, twin studies and other genetic analyses have established that approximately 80% of
schizophrenia risk is due to heritability, but at present only a small number of genes have been definitively
linked to this clearly polygenic disorder. Thus, the identification of additional genes that contribute to
schizophrenia risk can provide new insights about the disease and also suggest potential new avenues for
treatment. Recently, whole-exome analyses of an extensive set of multiplex schizophrenia families revealed
several mutations in the brain angiogenesis inhibitor 1 (BAI1) to be associated with schizophrenia. BAI1 is a
synaptic receptor known to regulate dendritic spines and synaptic plasticity, and the BAI1 mutations linked to
schizophrenia in these analyses are all missense mutations with extremely high CADD scores. We will assess
the effects of these schizophrenia-associated mutations on the trafficking and signaling activity of BAI1 in order
to determine how these mutations may be contributing to the development of schizophrenia. The signaling
studies will assess the effects of the mutations on both i) constitutive signaling activity by the receptor and
ii) signaling stimulated by co-expression of BAI1 with phospholipid scramblases. In parallel studies, we will
determine whether this scramblase-mediated potentiation of BAI1 signaling is due to externalization of
phosphatidylserine, a previously reported ligand for the extracellular domains of BAI1. Thus, the proposed
studies will shed new light on the fundamental biology of BAI1 while also assessing the functional effects of the
schizophrenia-associated BAI1 mutations, with the goal of facilitating the eventual targeting of this receptor by
small molecule therapeutics that may be useful new treatments for schizophrenia and other psychiatric
disorders.
!
!
项目摘要
精神分裂症是一种毁灭性的精神疾病,影响着美国约1%的人口。在过去的时间里
几十年来,双胞胎研究和其他遗传分析已经证实,大约80%的
精神分裂症的风险是由遗传性引起的,但目前只有少量基因被确定
与这种明显的多基因疾病有关。因此,识别其他有助于
精神分裂症的风险可以提供关于这种疾病的新见解,也可以为
治疗。最近,对一组广泛的多元化精神分裂症家庭的全基因组分析揭示了
脑血管生成抑制因子1(BAI1)的几个突变与精神分裂症有关。BAI1是一个
已知的突触受体调节树突棘和突触可塑性,BAI1突变与
这些分析中的精神分裂症都是错义突变,CADD得分极高。我们将评估
这些精神分裂症相关突变对BAI1转运和信号活性的影响
以确定这些突变可能如何导致精神分裂症的发展。信令
研究将评估突变对两个方面的影响:1)受体和
Ii)BAI1和磷脂扰乱酶共表达刺激的信号转导。在平行研究中,我们将
确定这种扰乱酶介导的BAI1信号增强是否是由于
磷脂酰丝氨酸,先前报道的BAI1胞外区的配体。因此,拟议的
研究将为BAI1的基础生物学提供新的线索,同时也将评估BAI1的功能影响
与精神分裂症相关的BAI1突变,目的是促进该受体的最终靶向
小分子疗法可能是治疗精神分裂症和其他精神疾病的有用的新疗法
精神错乱。
好了!
好了!
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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Randy A. Hall其他文献
PDZ interactions between PHLPP phosphatases and the NHERF scaffold
PHLPP 磷酸酶和 NHERF 支架之间的 PDZ 相互作用
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
M. Kunkel;E. Garcia;Randy A. Hall;A. Newton - 通讯作者:
A. Newton
Effects of cyclothiazide on synaptic responses in slices of adult and neonatal rat hippocampus.
环噻嗪对成年和新生大鼠海马切片突触反应的影响。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:1.7
- 作者:
John Larson;To;Randy A. Hall;Gary Lynch - 通讯作者:
Gary Lynch
Secタンパク質膜透過装置の活写にむけて
Sec蛋白膜渗透装置的实时成像
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Dan Zhu;Chenchen Li;Andrew M. Swanson;Rosa M. Villalba;Jidong Guo;Zhaobin Zhang;Shannon Matheny;Tatsuro Murakami;Jason R. Stephenson;Sarah Daniel;Masaki Fukata;Randy A. Hall;Jeffrey J. Olson;Gretchen N. Neigh;Yoland Smith;Donald G. Rainnie,;塚崎 智也,春山 隆充 ,菅野 泰功,田中 良樹 ,紺野 宏記 - 通讯作者:
塚崎 智也,春山 隆充 ,菅野 泰功,田中 良樹 ,紺野 宏記
Mini Review Adhesion G Protein-Coupled Receptors: Signaling, Pharmacology & Mechanisms of Activation
迷你回顾粘附 G 蛋白偶联受体:信号传导、药理学
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
K. Paavola;Randy A. Hall - 通讯作者:
Randy A. Hall
Mice lacking full length Adgrb1 (Bai1) exhibit social deficitsem,/em increased seizure susceptibility, and altered brain development
缺乏全长 Adgrb1(Bai1)的小鼠表现出社交缺陷、癫痫易感性增加和大脑发育改变。
- DOI:
10.1016/j.expneurol.2022.113994 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:4.200
- 作者:
Fu Hung Shiu;Jennifer C. Wong;Takahiro Yamamoto;Trisha Lala;Ryan H. Purcell;Sharon Owino;Dan Zhu;Erwin G. Van Meir;Randy A. Hall;Andrew Escayg - 通讯作者:
Andrew Escayg
Randy A. Hall的其他文献
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{{ truncateString('Randy A. Hall', 18)}}的其他基金
Disease-Associated Mutations and Ligand Activation of the Adhesion G Protein-Coupled Receptor ADGRB2
粘附 G 蛋白偶联受体 ADGRB2 的疾病相关突变和配体激活
- 批准号:
10811019 - 财政年份:2023
- 资助金额:
$ 23.4万 - 项目类别:
Control of Seizure and Migraine Susceptibility by GPR37L1
GPR37L1 控制癫痫和偏头痛易感性
- 批准号:
10449353 - 财政年份:2021
- 资助金额:
$ 23.4万 - 项目类别:
Control of Seizure and Migraine Susceptibility by GPR37L1
GPR37L1 控制癫痫和偏头痛易感性
- 批准号:
10279634 - 财政年份:2021
- 资助金额:
$ 23.4万 - 项目类别:
Control of Seizure and Migraine Susceptibility by GPR37L1
GPR37L1 控制癫痫和偏头痛易感性
- 批准号:
10651823 - 财政年份:2021
- 资助金额:
$ 23.4万 - 项目类别:
BAI2 mutation associated with a novel neurological disorder
BAI2 突变与新型神经系统疾病相关
- 批准号:
8877775 - 财政年份:2015
- 资助金额:
$ 23.4万 - 项目类别:
GPR37L1 mutation associated with a novel neurological disorder
GPR37L1 突变与新型神经系统疾病相关
- 批准号:
8871619 - 财政年份:2015
- 资助金额:
$ 23.4万 - 项目类别:
GPR37 & GPR37L1 signaling pathways promoting cell survival: relevance to stroke
探地雷达37
- 批准号:
8753503 - 财政年份:2014
- 资助金额:
$ 23.4万 - 项目类别:
GPR37 & GPR37L1 signaling pathways promoting cell survival: relevance to stroke
探地雷达37
- 批准号:
9464568 - 财政年份:2014
- 资助金额:
$ 23.4万 - 项目类别:
GPR37 & GPR37L1 signaling pathways promoting cell survival: relevance to stroke
探地雷达37
- 批准号:
9117648 - 财政年份:2014
- 资助金额:
$ 23.4万 - 项目类别:
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