Cerebellar stimulation for the treatment of dystonia: preclinical studies
小脑刺激治疗肌张力障碍:临床前研究
基本信息
- 批准号:8458057
- 负责人:
- 金额:$ 18.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-15 至 2014-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAffectAnimal ExperimentsAnimal ModelAnimalsAutopsyBasal GangliaBotulinum ToxinsBrainCase StudyCerebellar DiseasesCerebellumCerebral PalsyCervical DystoniaCervix NeoplasmsClinical ResearchDeep Brain StimulationDiseaseDyskinetic syndromeDystoniaDystonic DisorderElectric StimulationEpilepsyFOS geneFrequenciesFunctional ImagingGlobus PallidusGoalsHumanImageInjection of therapeutic agentLinkLocationMapsMeasuresModelingMovementMovement DisordersMusMuscleMuscle ContractionPatientsPharmaceutical PreparationsPhysiologic pulsePostureRattusReporterReportingSecondary DystoniaSignal TransductionSmooth MuscleTestingWidtheffective therapyexperiencemotor disordermouse modelnovelnovel therapeuticspalliativepre-clinicalpreclinical studysmall moleculesuccesstreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Dystonia is characterized by excessive involuntary muscle contractions that cause abnormal postures and twisting movements. Current treatments for dystonia are largely unsatisfactory or palliative. Small molecule drugs are ineffective in most patients. Botulinum toxin is effective but requires injection into affected muscles, limiting its ue to the treatment of dystonias that affect a small number of muscles. Deep brain stimulation (DBS) of the internal globus pallidus is another treatment option. Some patients, particularly those suffering from primary generalized dystonia experience tremendous benefits from pallidal DBS. However, many other patients, particularly those with secondary dystonias, experience little or no improvement, demonstrating a need for the identification and exploration of new treatment targets. Strong evidence implicates cerebellar abnormalities in dystonia and supports the idea that electrical stimulation of the cerebellum is an effective treatment for dystonia. Autopsy studies established a link between cervical dystonia and tumors of the cerebellum. Further, abnormal activity of the cerebellum is observed in many different forms of dystonia additionally, some cerebral palsy patients, who also often suffer from dystonia in addition to spasticity, have experienced improvement after cerebellar electrical stimulation. However, there are currently no studies examining the use of cerebellar stimulation in dystonia per se. Animal studies demonstrate that cerebellar abnormalities can cause dystonia. Abnormal cerebellar activity is observed in mouse and rat models of dystonia. In rat and mouse models, ablation of the cerebellum ameliorates dystonia. The effects of cerebellar stimulation have not yet been explored in animal models to test the idea that dystonia can be ameliorated using the non-ablative approach of electrical stimulation to interrupt abnormal signaling. Although cerebellar stimulation has been used in humans for decades, the use of cerebellar stimulation for the treatment of dystonia is surprisingly limited despite the strong evidence linking cerebellar dysfunction to dystonia in both human and animal studies. This proposal will systematically examine cerebellar stimulation for the treatment of dystonia in mouse models as preclinical proof-of-concept. The specific aims of this proposal are: Aim 1. To determine parameters of cerebellar stimulation that ameliorates dystonia. The effects of methodically varying stimulation parameters, including location, frequency, and amplitude and pulse width on dystonic and baseline activity are assessed in alert unrestrained mouse models of dystonia. Aim 2. to map the anatomical extent of stimulation. Because c-fos expression is routinely used to map electrical stimulation in brain, we will use the fos reporter TetTag mice to map extent of cerebellar stimulation. The success of this proposal will provide preclinical evidence to support an exploratory clinical study in humans for the use of cerebellar stimulation as a treatment for dystonia.
描述(由申请人提供):肌张力障碍的特征是过度的不自主肌肉收缩,导致异常姿势和扭曲运动。目前针对肌张力障碍的治疗大多不令人满意或只是姑息治疗。小分子药物对大多数患者无效。肉毒杆菌毒素有效,但需要注射到受影响的肌肉中,这限制了其治疗影响少数肌肉的肌张力障碍的用途。内部苍白球的深部脑刺激(DBS)是另一种治疗选择。一些患者,特别是那些患有原发性全身性肌张力障碍的患者,从苍白球 DBS 中获得了巨大的好处。然而,许多其他患者,特别是那些患有继发性肌张力障碍的患者,几乎没有或根本没有改善,这表明需要确定和探索新的治疗靶点。强有力的证据表明肌张力障碍涉及小脑异常,并支持小脑电刺激是肌张力障碍有效治疗的观点。尸检研究确定了颈部肌张力障碍和小脑肿瘤之间的联系。此外,在许多不同形式的肌张力障碍中都观察到小脑的异常活动,此外,一些除痉挛外还经常患有肌张力障碍的脑瘫患者在小脑电刺激后得到了改善。然而,目前还没有研究检查小脑刺激在肌张力障碍中的应用。动物研究表明,小脑异常可导致肌张力障碍。在肌张力障碍小鼠和大鼠模型中观察到小脑活动异常。在大鼠和小鼠模型中,小脑消融可改善肌张力障碍。尚未在动物模型中探索小脑刺激的影响,以测试使用非消融性电刺激方法中断异常信号传导可以改善肌张力障碍的想法。尽管小脑刺激已在人类中使用了几十年,但尽管在人类和动物研究中都有强有力的证据表明小脑功能障碍与肌张力障碍有关,但小脑刺激用于治疗肌张力障碍的用途却出人意料地有限。该提案将系统地检查小脑刺激在小鼠模型中治疗肌张力障碍的作用,作为临床前概念验证。该提案的具体目标是: 目标 1. 确定改善肌张力障碍的小脑刺激参数。在警觉、不受约束的肌张力障碍小鼠模型中,评估有条不紊地改变刺激参数(包括位置、频率、幅度和脉冲宽度)对肌张力障碍和基线活动的影响。目标 2. 绘制刺激的解剖范围。由于 c-fos 表达通常用于绘制大脑中的电刺激图,因此我们将使用 fos 报告基因 TetTag 小鼠来绘制小脑刺激的程度。该提案的成功将为支持利用小脑刺激治疗肌张力障碍的人体探索性临床研究提供临床前证据。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
ELLEN J. HESS其他文献
ELLEN J. HESS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('ELLEN J. HESS', 18)}}的其他基金
Neuronal Mechanisms underlying sex differences in dystonia
肌张力障碍性别差异背后的神经机制
- 批准号:
10701752 - 财政年份:2022
- 资助金额:
$ 18.82万 - 项目类别:
Neuronal Mechanisms underlying sex differences in dystonia
肌张力障碍性别差异背后的神经机制
- 批准号:
10518475 - 财政年份:2022
- 资助金额:
$ 18.82万 - 项目类别:
Neuronal Mechanisms underlying sex differences in dystonia
肌张力障碍性别差异背后的神经机制
- 批准号:
10784385 - 财政年份:2022
- 资助金额:
$ 18.82万 - 项目类别:
Striatal cell-type specific molecular adaptations in a mouse model of dystonia
肌张力障碍小鼠模型中纹状体细胞类型特异性分子适应
- 批准号:
10057917 - 财政年份:2020
- 资助金额:
$ 18.82万 - 项目类别:
Dopamine neurotransmission in a model of DOPA-responsive dystonia
多巴反应性肌张力障碍模型中的多巴胺神经传递
- 批准号:
9481589 - 财政年份:2017
- 资助金额:
$ 18.82万 - 项目类别:
Dopamine neurotransmission in a model of DOPA-responsive dystonia
多巴反应性肌张力障碍模型中的多巴胺神经传递
- 批准号:
9203641 - 财政年份:2015
- 资助金额:
$ 18.82万 - 项目类别:
Dopamine neurotransmission in a model of DOPA-responsive dystonia
多巴反应性肌张力障碍模型中的多巴胺神经传递
- 批准号:
8887950 - 财政年份:2015
- 资助金额:
$ 18.82万 - 项目类别:
Cerebellar stimulation for the treatment of dystonia: preclinical studies
小脑刺激治疗肌张力障碍:临床前研究
- 批准号:
8269318 - 财政年份:2012
- 资助金额:
$ 18.82万 - 项目类别:
Generation of a mouse model of L-DOPA-responsive dystonia (DRD)
L-DOPA 反应性肌张力障碍 (DRD) 小鼠模型的生成
- 批准号:
7765651 - 财政年份:2007
- 资助金额:
$ 18.82万 - 项目类别:
Generation of a mouse model of episodic ataxia type 2 (EA2)
2 型发作性共济失调 (EA2) 小鼠模型的生成
- 批准号:
7313608 - 财政年份:2007
- 资助金额:
$ 18.82万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 18.82万 - 项目类别:
Research Grant