Heterotrimeric G-protein regulation of neurotransmission in C. elegans
异源三聚体 G 蛋白对线虫神经传递的调节
基本信息
- 批准号:7219194
- 负责人:
- 金额:$ 4.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-02-01 至 2010-01-31
- 项目状态:已结题
- 来源:
- 关键词:1,2-diacylglycerolAdultAffectAnabolismAnimal FeedBehaviorBiochemicalBiologicalBiological AssayBrainCaenorhabditis elegansCell divisionCellsDiglyceridesEmbryoEndocytosisEnzymesEukaryotaEukaryotic CellExocytosisFamily memberFrequenciesG-Protein-Coupled ReceptorsGTP-Binding ProteinsGene ExpressionGenesGeneticGenetic ScreeningGenetic TranscriptionGuanosine Triphosphate PhosphohydrolasesHeterotrimeric GTP-Binding ProteinsHumanHydrolysisImageryIn SituInositol 1,4,5-TrisphosphateIon ChannelLightMapsMicroarray AnalysisMicrotubulesMitoticMitotic spindleMolecularMolecular ProfilingMuscle ContractionMuscle TremorsMutationNematodaNervous system structureNeurodegenerative DisordersNeuronsParkinson DiseasePerceptionPharmacologic SubstancePhenotypePhosphatidylinositolsPhospholipase CPhospholipidsPositioning AttributeProtein BiosynthesisRateRegulationResearchSecond Messenger SystemsSeizuresSensorySerotoninSignal PathwaySignal TransductionSoilSuppressor MutationsSynapsesSynaptic VesiclesSyndromeTestingTransducersTryptophan 5-monooxygenasebasecell growthcell motilityeggin vivomembermutantneurotransmissionnovelphosphatidylinositol phosphatereceptorresearch studyresponsesecond messengersensor
项目摘要
DESCRIPTION (provided by applicant): Signaling through heterotrimeric GTPases (G-proteins) activates cellular effector enzymes and ion channels to regulate cell growth, mitotic division, and sensory perception. G-protein coupled receptors are among the most commonly used signal transducers in eukaryotes and are the targets of about half of prescribed Pharmaceuticals. The soil nematode, Caenorhabditis elegans, offers many experimental advantages to investigate the conserved features of heterotrimeric G-protein signaling. In embryos, G- proteins regulate microtubule forces that control mitotic spindle positioning during asymmetric cell division. In adults, G-proteins coordinate animal feeding, motility, and other behaviors by altering synaptic activity and the frequency of muscle contractions. These behaviors offer convenient and quantitative assays to study intracellular and intercellular signaling genetically. Through three independent lines of experimentation, I will study the molecular and cellular consequences of signaling through two G-proteins, EGL-30 (Gctq) and GOA-1 (Ga0). Activated EGL-30 interacts with EGL- 8, the phosphatidylinositol (4,5) bisphosphate (PlPz)-specific Phospholipase C (p) family member. Hydrolysis of PIP? by EGL-8 releases the second messengers inositol 1,4,5-triphosphate (IP3) and 1,2- diacylglycerol (DAG). In contrast, direct effectors of activated GOA-1 remain unknown. To find these, I will isolate mutants that suppress hyperactivated GOA-1 signaling phenotypes. One suppressor has already been mapped by members of the Koelle lab, and I will map additional suppressor mutations, determine how the encoded factors regulate signaling, and test whether they act as direct effectors for GOA-1. Second, to study how GOA-1 antagonizes EGL-30 signaling to modulate synaptic activity, I will visualize EGL-8 activity in vivo using established fluorescent sensors of Ca+2 and specific phospholipids. I will test how mutations that impair or stimulate inhibitory GOA-1 signaling affect the behavior and distribution of these indicators. These in situ biochemical experiments will reveal the cell biological consequences of the signaling pathways defined genetically. Finally, to find genes whose expression is regulated by signaling, I will compare gene expression profiles in goa-1 and egl-30 mutants by microarray analysis. This research will shed light on how the nervous system controls the frequency of muscle contractions. As these functions are perturbed during human brain seizures, muscle tremors, and neurodegenerative diseases such as Parkinson's, these studies should inform a rational basis for targeted therapies.
描述(由申请人提供):通过异三聚体GTPases(G蛋白)信号传导激活细胞效应子酶和离子通道,以调节细胞生长,有丝分裂分裂和感觉感知。 G蛋白偶联受体是真核生物中最常用的信号传感器之一,是大约一半的规定药物的靶标。土壤线虫秀丽隐杆线虫具有许多实验优势,可以研究异三聚体G蛋白信号的保守特征。在胚胎中,g-蛋白调节微蛋白在不对称细胞分裂过程中控制有丝分裂纺锤体定位的微管力。在成年人中,G蛋白通过改变突触活动和肌肉收缩的频率来协调动物的进食,运动性和其他行为。这些行为为细胞内和细胞间信号的遗传传导提供了方便和定量的测定。通过三个独立的实验线,我将通过两个G蛋白EGL-30(GCTQ)和GOA-1(GA0)研究信号传导的分子和细胞后果。活化的EGL-30与EGL-8,磷脂酰肌醇(4,5)双磷酸(PLPZ) - 特异性磷脂酶C(P)家族成员相互作用。 PIP的水解?通过EGL-8释放第二个信使肌醇1,4,5-三磷酸(IP3)和1,2-二酰基甘油(DAG)。相比之下,活化的果阿-1的直接效应子仍然未知。为了找到这些,我将分离抑制过度活化的GOA-1信号表型的突变体。一个抑制器已经由Koelle Lab的成员绘制,我将绘制其他抑制剂突变,确定编码因子如何调节信号传导,并测试它们是否充当GOA-1的直接效应子。其次,为了研究GOA-1如何拮抗EGL-30信号传导以调节突触活动,我将使用既定的Ca+2和特定磷脂的荧光传感器在体内可视化EGL-8活性。我将测试损害或刺激抑制性GOA-1信号的突变如何影响这些指标的行为和分布。这些原位生化实验将揭示基因定义的信号传导途径的细胞生物学后果。最后,为了找到通过信号传导调节表达的基因,我将通过微阵列分析比较GOA-1和EGL-30突变体中的基因表达谱。这项研究将阐明神经系统如何控制肌肉收缩的频率。由于这些功能在人脑癫痫发作期间受到干扰,肌肉震颤和诸如帕金森氏病等神经退行性疾病,因此这些研究应为有针对性疗法的合理基础提供理性的基础。
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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Kevin Michael Collins其他文献
Kevin Michael Collins的其他文献
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{{ truncateString('Kevin Michael Collins', 18)}}的其他基金
Neuromodulator signaling and activity in the C. elegans egg-laying circuit
线虫产卵回路中的神经调节信号和活动
- 批准号:
10507984 - 财政年份:2022
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit
线虫产卵回路中的神经调节信号和活动
- 批准号:
10599389 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit.
线虫产卵回路中的神经调节信号和活动。
- 批准号:
8915782 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit.
线虫产卵回路中的神经调节信号和活动。
- 批准号:
9087351 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit
线虫产卵回路中的神经调节信号和活动
- 批准号:
10337535 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit
线虫产卵回路中的神经调节信号和活动
- 批准号:
10398019 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit
线虫产卵回路中的神经调节信号和活动
- 批准号:
10535094 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit.
线虫产卵回路中的神经调节信号和活动。
- 批准号:
8814527 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Neuromodulator signaling and activity in the C. elegans egg-laying circuit
线虫产卵回路中的神经调节信号和活动
- 批准号:
9813142 - 财政年份:2014
- 资助金额:
$ 4.48万 - 项目类别:
Heterotrimeric G-protein regulation of neurotransmission in C. elegans
异源三聚体 G 蛋白对线虫神经传递的调节
- 批准号:
7556778 - 财政年份:2007
- 资助金额:
$ 4.48万 - 项目类别:
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