Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter
Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter
批准号:
7730519
负责人:
ANITA SIDHU
金额:
$38.38万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-07-16 至 2011-06-30
关键词:
ActinsAdultAffectAftercareAgeAmoxapineAnimalsAntibodiesAntidepressive AgentsApplications GrantsAreaAttentionAutopsyBehaviorBehavioralBindingBinding ProteinsBrainBreast Cancer CellBreast CarcinomaBuffersCell NucleusCell surfaceCellsCharacteristicsChronicCo-ImmunoprecipitationsComplementary DNAComplexComputer softwareCytoplasmCytoskeletal ProteinsCytoskeletonDactinomycinDataDesipramineDevelopmentDoseDown-RegulationDrug AddictionDrug Delivery SystemsDrug abuseEquilibriumFunctional disorderGamma synucleinGenetic TranscriptionGrantGuanosine TriphosphateHomeostasisHumanImipramineImmunoprecipitationIn VitroInbred WKY RatsIncidenceIndividualInferior frontal gyrusKnockout MiceLabelLaboratoriesLeadLinkMaintenanceMalignant Epithelial CellMeasuresMediatingMembraneMessenger RNAMethionineMicrotubulesModelingMolecularMood DisordersMoodsMusNeurodegenerative DisordersNeuronsNocodazoleNorepinephrineNuclearNucleotidesNylonsOccupationsParkinson DiseasePatientsPharmaceutical PreparationsPhysiologic pulseProtein FamilyProteinsPublishingRNARattusReactionReagentRegulationRelative (related person)ReportingResearchResearch DesignReverse Transcriptase Polymerase Chain ReactionRoleRun-On AssaysSeriesSignal TransductionSleepSynaptic plasticitySynaptosomesSynuclein FamilySystemTimeTissuesTransgenic MiceTransgenic OrganismsTubulinVision DisordersWestern BlottingWistar Ratsalpha synucleinclinically relevantdepressiondepressive symptomsfrontal lobehormone regulationin vitro Modelin vivoin vivo ModelinsightmRNA Stabilitymemberneurochemistryneurogenesisneurotransmissionnoradrenaline transporternoradrenergicnoveloverexpressionpresynapticpromoterprotein expressionreboxetineresponserestorationsynucleinsynucleinopathytau Proteinstraffickingtrizolvigilance
中文摘要
人类大脑中异常的去甲肾上腺素[NE]神经传递与情绪障碍、抑郁、药物成瘾和神经退行性疾病有关。-突触核蛋白[-Syn]是突触核蛋白家族的一员,在单胺能神经元中表达,但其在脑中的功能尚不清楚。我们已经证明-Syn可以通过与微管[MT]细胞骨架的相互作用来调节NE转运体[Net]的功能和运输。我们在这里表明,-SYN也可以调节这些网络活动。这种由-SYN进行的调制是网络所独有的。在抑郁症大鼠模型中,存在-Syn的过度表达,导致Net的功能和运输受到失调,并且对诺可达唑[MT破坏稳定剂]的影响没有反应,这可能是由于-Syn/Net复合体与MT细胞骨架的紧密结合所致。用地塞帕明[一种Net阻滞剂]慢性治疗这些动物,降低了-Syn蛋白的表达,同时提高了-Syn水平,使Net受到-Syn的适当调节,并完全恢复了诺可达唑的敏感性。在抑郁症患者的尸检脑中,我们还发现-Syn过表达,这增加了-Syn在人类抑郁症的发生和维持中的作用的临床相关性。
我们假设-SYN作为一种前抑郁药,-SYN/-SYN表达水平的失衡是抑郁症发生的核心。当过度表达时,-SYN凌驾于-SYN对NET的规范调节之上。
因此,靶向-syn表达水平可能是控制人类抑郁症的关键。我们将在此详细研究地昔帕明在体外和体内模型中降低-SYN水平的细胞和分子机制,在存在或不存在-SYN的情况下,单独表达-SYN或同时表达-SYN和Net。我们还将在体外模型中分析其他净抗抑郁药降低-SYN表达的机制。最后,我们将在-syn过表达的转基因小鼠和-syn基因敲除小鼠中测量神经化学和行为对净抗抑郁药的反应。通过这些研究,我们将能够评估-Syn表达被调控的机制,并确定这种调控在抑郁症发生中的生理病理相关性。
英文摘要
Aberrant norepinephrine [NE] neurotransmission in the human brain is linked to mood disorders, depression, drug addiction and neurodegenerative diseases. -synuclein [-Syn], a member of the synuclein family of proteins, is expressed in monoaminergic neurons, but its function in the brain is not known. We have shown that -Syn can modulate the function and trafficking of the NE transporter [NET], through interactions with the microtubule [MT] cytoskeleton. We show here that -Syn can also regulate these NET activities. Such modulation by -Syn is unique to NET. In a rat model of depression, there is overexpression of -Syn, causing NET function and trafficking to be dysregulated and unresponsive to the effects of nocodazole [a MT destabilizing agent], probably due to tight binding of the -Syn/NET complex to the MT cytoskeleton. Chronic treatment of these animals with desipramine [a NET blocker] reduces -Syn protein expression, while increasing -Syn levels, permitting NET to be appropriately regulated by -Syn, with full restoration of nocodazole sensitivity. In postmortem brains from patients with depression, we also show that -Syn is overexpressed, adding clinical relevance for a role for -Syn in the genesis and maintenance of depression in humans.
We hypothesize that -Syn acts as a prodepressant, and that imbalances in -Syn/-Syn expression levels is central to the genesis of depression. When overexpressed, -Syn overrides the normative regulation of NET by -Syn.
Therefore, targeting -Syn expression levels may be key to controlling depression in humans. We will investigate here in detail the cellular and molecular mechanisms by which desipramine reduces -Syn levels in both in vitro and in vivo models, which express either -Syn alone or both -Syn and NET, in the presence or absence of -Syn. We will also analyze the mechanisms by which other NET antidepressants decrease -Syn expression in in vitro models. Finally, we will measure neurochemical and behavioral responses to NET antidepressants in -Syn overexpressing transgenic mice, as well as in -Syn knock-out mice. From these studies we will be able to assess the mechanisms by which -Syn expression is regulated as well as ascertain the physiopathological relevance of such regulation in the genesis of depression.
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会议论文
Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter
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批准号:7895095
-
项目类别:
-
资助金额:$38.38万
-
财政年份:2009
-
负责人:ANITA SIDHU
-
依托单位:
Modulation of Serotonergic Transporters
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批准号:7683377
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项目类别:
-
资助金额:$4.0万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Mechanisms of Tauopathies and Synucleopathies
-
批准号:7364624
-
项目类别:
-
资助金额:$31.86万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Mechanisms of Tauopathies and Synucleopathies
-
批准号:7266462
-
项目类别:
-
资助金额:$33.64万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Mechanisms of Tauopathies and Synucleopathies
-
批准号:7577476
-
项目类别:
-
资助金额:$31.86万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Mechanisms of Tauopathies and Synucleopathies
-
批准号:8522657
-
项目类别:
-
资助金额:$9.0万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Modulation of Serotonergic Transporters
-
批准号:7766980
-
项目类别:
-
资助金额:$30.97万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Modulation of Serotonergic Transporters
-
批准号:7350195
-
项目类别:
-
资助金额:$30.97万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Modulation of Serotonergic Transporters
-
批准号:7574438
-
项目类别:
-
资助金额:$30.97万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Mechanisms of Tauopathies and Synucleopathies
-
批准号:7795118
-
项目类别:
-
资助金额:$31.54万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Modulation of Serotonergic Transporters
-
批准号:7213087
-
项目类别:
-
资助金额:$32.35万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
Mechanisms of Tauopathies and Synucleopathies
-
批准号:8039094
-
项目类别:
-
资助金额:$30.32万
-
财政年份:2007
-
负责人:ANITA SIDHU
-
依托单位:
NMR STUDIES ON BRAIN METABOLISM
-
批准号:7420598
-
项目类别:
-
资助金额:$0.92万
-
财政年份:2006
-
负责人:ANITA SIDHU
-
依托单位:
TRAINING IN THE USE OF BRUKER AND VARIAN SPECTROMETERS AND NMR
-
批准号:7420602
-
项目类别:
-
资助金额:$0.01万
-
财政年份:2006
-
负责人:ANITA SIDHU
-
依托单位:
TRAINING IN THE USE OF BRUKER AND VARIAN SPECTROMETERS AND NMR
-
批准号:6977419
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2004
-
负责人:ANITA SIDHU
-
依托单位:
NMR STUDIES ON BRAIN METABOLISM
-
批准号:6977415
-
项目类别:
-
资助金额:$0.82万
-
财政年份:2004
-
负责人:ANITA SIDHU
-
依托单位:
SYNUCLEOPATHIES IN NEURODEGENERATION
-
批准号:7243775
-
项目类别:
-
资助金额:$2.34万
-
财政年份:2003
-
负责人:ANITA SIDHU
-
依托单位:
SYNUCLEOPATHIES IN NEURODEGENERATION
-
批准号:7090702
-
项目类别:
-
资助金额:$35.43万
-
财政年份:2003
-
负责人:ANITA SIDHU
-
依托单位:
SYNUCLEOPATHIES IN NEURODEGENERATION
-
批准号:6799583
-
项目类别:
-
资助金额:$31.62万
-
财政年份:2003
-
负责人:ANITA SIDHU
-
依托单位:
SYNUCLEOPATHIES IN NEURODEGENERATION
-
批准号:6919914
-
项目类别:
-
资助金额:$31.62万
-
财政年份:2003
-
负责人:ANITA SIDHU
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依托单位:
海外基金