The Role of Striatal Cholinergic Interneurons in Dystonia
纹状体胆碱能中间神经元在肌张力障碍中的作用
基本信息
- 批准号:10543837
- 负责人:
- 金额:$ 61.69万
- 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:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAdult-Onset DystoniasAffectAgeAnalysis of VarianceAnimal ModelBindingBiochemicalBlepharospasmBody RegionsBrainBrain regionCerebellumCervicalCharacteristicsCholinergic ReceptorsClinicalControl GroupsCorpus striatum structureDataDevelopmentDiseaseDopamineDrug TargetingDystoniaEmployment StatusFocal DystoniasFunctional Magnetic Resonance ImagingFunctional disorderFutureGenotypeGoalsHeterogeneityHumanInterneuron functionInterneuronsKnowledgeLarynxLimb DystoniaMagnetic Resonance ImagingMeasurementMeasuresMediatingMethodsMissionModelingMolecularMultimodal ImagingMuscleNeuronsNeurotransmittersParticipantPathogenicityPathway interactionsPersonsPharmaceutical PreparationsPhenotypePlayPositron-Emission TomographyPublic HealthQuality of lifeResearchResearch PersonnelResearch PriorityRestRoleSeveritiesSignal TransductionSubgroupSystemTestingThalamic structureTherapeutic InterventionTranslatingUnited States National Institutes of HealthUpper Extremityacetylcholine transportercholinergiccomparison controlcomparison groupdisabilityeffective therapygene discoveryin vivoinnovationinterestmotor controlnetwork dysfunctionneuroimagingneuroimaging markernew therapeutic targetnovelpresynapticradioligandregional differencesexsymptomatic improvementtherapeutic targetuptake
项目摘要
PROJECT SUMMARY
There is a fundamental gap in understanding the pathophysiology of isolated adult-onset dystonia due to
genotypic and phenotypic heterogeneity. Determining common pathophysiologic mechanisms across dystonia
subtypes is a critical step toward developing more generalizable and effective therapies. Emerging evidence
points to striatal cholinergic interneurons (ChIs) playing a key role in the pathophysiology of dystonia, including
biochemical and network-level dysfunction. In addition to offering a common therapeutic target, our findings
are likely to benefit gene discovery and research on other disabling, less common forms of dystonia. Over the
long term, results could guide researchers to perform greater in depth histopathological and biochemical studies
in the brain that can lead to identification of new targets for therapeutic intervention. Our goal is to apply a
recently developed PET radioligand, [18F]VAT, which possesses high selectivity for vesicular acetylcholine
transporters, to investigate striatal ChIs. Structural and resting state functional MRI will examine the
relationship of striatal ChIs to related brain networks across different focal dystonia subtypes. Identification of
network-level changes across dystonia subtypes will provide better understanding of common pathophysiology
and could potentially provide means to assess target engagement for future therapeutic interventions. The
central hypothesis is that striatal ChIs contribute to a common pathophysiological mechanism in humans with
isolated adult-onset focal dystonia, and that cholinergic integrity relates to striatal functional connectivity and
clinical features of dystonia. The rationale for the proposed research is the likely involvement of striatal ChIs in
a) normal motor control and b) animal models of dystonia. ChIs are autonomously active and mediate a baseline
presynaptic inhibitory tone on striatal medium spiny neurons against the excitatory cortical drive, likely via
modulation of dopamine release via presynaptic cholinergic receptors on nigrostriatal dopaminergic terminals.
They also receive input from intralaminar thalamic neurons innervated by cerebellar afferents, that when
dysfunctional may contribute to dystonic phenotypes. Thus, ChIs may contribute to a common pathogenic
mechanism involving cortico-striata-thalamic or cerebello-thalamo-striatal networks. This hypothesis will be
tested by pursuing three specific aims: Determine if 1) dysfunction of striatal ChIs is a common
mechanism across isolated dystonia subtypes; 2) common aberrations in functional striatal
brain networks underlie the isolated dystonia subtypes; 3) clinical characteristics relate to
markers of ChIs and brain network dysfunction across different isolated adult-onset focal
dystonias. This approach is innovative as it uses comprehensive multimodal imaging to investigate novel PET-
measured cholinergic integrity and related functional networks. The proposed research is significant because it
is expected to critically advance the understanding of dystonia. Ultimately, such knowledge may provide critical
rationale to identify and test new therapeutic targets and better understand other disabling forms of dystonia.
项目摘要
在理解孤立的成人发作性肌张力障碍的病理生理学方面存在根本性的差距,
基因型和表型异质性。确定肌张力障碍的常见病理生理机制
亚型是开发更普遍和有效的治疗方法的关键一步。新出现的证据
指出纹状体胆碱能中间神经元(ChI)在肌张力障碍的病理生理学中发挥关键作用,包括
生化和网络水平的功能障碍。除了提供一个共同的治疗目标,我们的研究结果
很可能有利于基因发现和其他致残的研究,不太常见的肌张力障碍。来
从长远来看,研究结果可以指导研究人员进行更深入的组织病理学和生物化学研究
这可能会导致识别治疗干预的新靶点。我们的目标是应用一个
最近开发的PET放射性配体,[18 F]VAT,其对囊泡乙酰胆碱具有高选择性
转运蛋白,以研究纹状体ChIs。结构和静息状态功能MRI将检查
纹状体ChI与不同局灶性肌张力障碍亚型相关脑网络的关系。鉴定
肌张力障碍亚型之间的网络水平变化将提供对常见病理生理学的更好理解
并且可以潜在地提供用于评估未来治疗干预的目标接合的手段。的
中心假设是纹状体ChI有助于人类的共同病理生理机制,
孤立的成人发作的局灶性肌张力障碍,胆碱能完整性与纹状体功能连接有关,
肌张力障碍的临床特征。这项研究的基本原理是纹状体ChI可能参与了
a)正常的运动控制和B)肌张力障碍的动物模型。ChI是自主活动的,
突触前抑制性音调对纹状体中型多棘神经元对兴奋性皮层驱动,可能通过
通过黑质纹状体多巴胺能末梢上的突触前胆碱能受体调节多巴胺释放。
它们还接受由小脑传入神经支配的丘脑板内神经元的输入,
功能障碍可能导致张力障碍表型。因此,ChIs可能导致一种常见的致病性
涉及皮质-纹状体-丘脑或小脑-丘脑-纹状体网络的机制。这一假设将是
通过追求三个具体目标进行测试:确定1)纹状体ChIs功能障碍是否是常见的
孤立性肌张力障碍亚型的机制; 2)功能性纹状体的常见畸变
脑网络是孤立性肌张力障碍亚型的基础; 3)临床特征与
ChIs和脑网络功能障碍的标志物在不同孤立的成人发病灶性脑梗死中的作用
肌张力障碍这种方法是创新的,因为它使用全面的多模态成像来研究新的PET-
测量胆碱能完整性和相关功能网络。这项研究意义重大,因为它
有望极大地推进对肌张力障碍的理解。最终,这些知识可以提供关键的
确定和测试新的治疗靶点并更好地了解其他失能形式的肌张力障碍的基本原理。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Scott Allen Norris其他文献
Scott Allen Norris的其他文献
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{{ truncateString('Scott Allen Norris', 18)}}的其他基金
The Role of Striatal Cholinergic Interneurons in Dystonia
纹状体胆碱能中间神经元在肌张力障碍中的作用
- 批准号:
10343290 - 财政年份:2022
- 资助金额:
$ 61.69万 - 项目类别:
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