Developing novel treatment strategies for Spinocerebellar ataxia type 1
开发 1 型脊髓小脑共济失调的新治疗策略
基本信息
- 批准号:9226821
- 负责人:
- 金额:$ 23.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2018-11-30
- 项目状态:已结题
- 来源:
- 关键词:Abnormal coordinationAffectAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisAngiogenic FactorAreaAtaxiaAttentionBehavioralBiochemicalBiocompatible MaterialsBiologicalBrainBrain StemCAG repeatCerebellar degenerationCessation of lifeClinicClinical TrialsComplexDataDiseaseDisease ProgressionEnvironmentFaceFamilyFunctional disorderGenesGeneticGenetic TranscriptionGlutamineGoalsGrantGrowth FactorHippocampus (Brain)Huntington DiseaseInheritedInternationalKnock-in MouseModelingMotorMotor NeuronsMusMutateNamesNanotechnologyNerve DegenerationNeuraxisNeurodegenerative DisordersNeuronsParalysedParkinson DiseasePathologicPathologyPatientsPeptidesPharmacologyPhenotypePhysiologicalPlayPopulationPreclinical TestingPropertyProteinsPurkinje CellsReagentRecombinant Vascular Endothelial Growth FactorRecombinantsResearchRoleSignal TransductionSpinocerebellar AtaxiasSymptomsTestingTherapeuticTherapeutic AgentsTherapeutic EffectToxic effectTreatment ProtocolsType 1 Spinocerebellar AtaxiaVEGFA geneVascular Endothelial Growth FactorsWorkaging populationaqueousataxin-1basecostcytokinedesigndosagehuman diseaseimaging biomarkerimmunogenicinnovationmiddle agemisfolded proteinmutantnanonanomedicinenanoparticleneurotrophic factornovelnovel therapeuticsoutcome forecastoverexpressionpeptidomimeticspolyglutaminereduce symptomsspinal and bulbar muscular atrophytreatment strategy
项目摘要
The lack of viable treatments for neurodegenerative diseases is becoming an increasingly pressing problem,
as an ever-larger proportion of our population advances in years and becomes susceptible to these so far
intractable conditions. The challenges are many: the brain is particularly delicate, complex, and inaccessible.
We have been studying a particular neurodegenerative disease, Spinocerebellar ataxia type 1 (SCA1), which
is one of a family of late-onset proteinopathies and thus a close cousin to Huntington's disease, Parkinson's,
and amyotrophic lateral sclerosis. We made the unexpected discovery that ATXN1, the protein that is mutated
in SCA1, directly regulates the expression of the angiogenic and neurotrophic cytokine VEGF; moreover, when
mutated it causes the levels of VEGF to be abnormally low in the SCA1 mouse brain, causing pathological
changes in the microvasculature as well as in the dendritic arborization of neurons. We have also
demonstrated that these pathologies, and the motor incoordination that results from them, can be reversed by
either genetic or pharmacologic replenishment of VEGF. There are severe limitations to the recombinant
VEGF we had used in our study, however: it is extremely costly to manufacture, it is biologically unstable, and
it is immunogenic. For these reasons, we have spent the past few years developing a completely new VEGF
reagent with the help of our collaborator Dr. Sam Stupp, an internationally recognized expert in the field of
nanotechnology and a collaborator on this grant. The reagent is a VEGF peptide amphiphile (VEGF-PA) that is
less immunogenic and is designed to self-assemble in an aqueous environment into stable peptide amphiphile
nanoparticles. Our preliminary data indicate that VEGF-PA is effective in SCA1 mice. In this proposal we will
establish the feasibility of using VEGF-PA nano-peptide as a biochemically stable and inexpensive alternative
to recombinant VEGF for long-term therapy for cerebellar degeneration. We hope that our studies will advance
this nanotechnology toward clinical trials for treating SCA1. Given that deficiency in VEGF has been implicated
in a wide range of neurodegenerative diseases including motor neuron disorders and Parkinson's disease, our
work in SCA1 has the potential to revolutionize treatment for neurodegeneration. Moreover, these studies will
pave the way for nanomedicine based treatments to be used to replace other neurotrophic factors, with broad
ramifications for potential therapies for many diseases.
神经退行性疾病缺乏可行的治疗方法正成为一个日益紧迫的问题,
随着我们人口中越来越多的人在年龄上的增长,到目前为止,
棘手的情况。挑战很多:大脑特别脆弱,复杂,难以接近。
我们一直在研究一种特殊的神经退行性疾病,脊髓小脑共济失调1型(SCA 1),
是晚发性蛋白质病家族中的一员,因此是亨廷顿病、帕金森病
和肌萎缩侧索硬化症我们意外地发现ATXN 1,突变的蛋白质
在SCA 1中,直接调节血管生成和神经营养细胞因子VEGF的表达;此外,当
突变导致SCA 1小鼠脑中VEGF水平异常低,导致病理性
微血管系统的变化以及神经元的树突状分支。我们还
证明了这些病理,以及由它们引起的运动不协调,可以通过
VEGF的遗传或药理学补充。重组体存在严重的局限性,
然而,我们在研究中使用的VEGF:制造成本极高,生物学不稳定,
它具有免疫原性。由于这些原因,我们在过去的几年里开发了一种全新的VEGF,
在我们的合作者Sam Stupp博士的帮助下,该试剂是国际公认的试剂领域的专家。
纳米技术和一个合作者。该试剂是VEGF肽两亲物(VEGF-PA),
免疫原性较低且被设计成在水性环境中自组装成稳定肽两亲物
纳米粒子我们的初步数据表明VEGF-PA在SCA 1小鼠中是有效的。在本提案中,我们将
建立使用VEGF-PA纳米肽作为生物化学稳定和廉价替代品的可行性
重组VEGF长期治疗小脑变性。我们希望我们的研究能有所进展
将这项纳米技术用于治疗SCA 1的临床试验。鉴于VEGF的缺乏与
在广泛的神经退行性疾病,包括运动神经元疾病和帕金森病,我们的
SCA 1的工作有可能彻底改变神经变性的治疗。此外,这些研究将
为纳米医学为基础的治疗铺平了道路,用于取代其他神经营养因子,广泛
对许多疾病的潜在疗法的影响。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Puneet Opal其他文献
Puneet Opal的其他文献
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{{ truncateString('Puneet Opal', 18)}}的其他基金
VEGF-Mimetic Supramolecular Nanoparticles for Treating Spinocerebellar Ataxia Type 1
VEGF 模拟超分子纳米颗粒用于治疗 1 型脊髓小脑共济失调
- 批准号:
10578485 - 财政年份:2023
- 资助金额:
$ 23.53万 - 项目类别:
Equipment Supplement: Understanding the Cellular Basis of Movement Disorders
设备补充:了解运动障碍的细胞基础
- 批准号:
10755946 - 财政年份:2023
- 资助金额:
$ 23.53万 - 项目类别:
Elucidating cellular mechanisms underlying neurodegeneration
阐明神经变性的细胞机制
- 批准号:
10647869 - 财政年份:2022
- 资助金额:
$ 23.53万 - 项目类别:
Elucidating cellular mechanisms underlying neurodegeneration
阐明神经变性的细胞机制
- 批准号:
10435954 - 财政年份:2022
- 资助金额:
$ 23.53万 - 项目类别:
Understanding the cellular basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
8876831 - 财政年份:2013
- 资助金额:
$ 23.53万 - 项目类别:
Understanding the cellular basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
8631893 - 财政年份:2013
- 资助金额:
$ 23.53万 - 项目类别:
Understanding the Cellular Basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
10630308 - 财政年份:2013
- 资助金额:
$ 23.53万 - 项目类别:
Understanding the Cellular Basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
10403448 - 财政年份:2013
- 资助金额:
$ 23.53万 - 项目类别:
Understanding the cellular basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
8719191 - 财政年份:2013
- 资助金额:
$ 23.53万 - 项目类别:
Understanding the Cellular Basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
10160963 - 财政年份:2013
- 资助金额:
$ 23.53万 - 项目类别:
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