Novel chaperones and neurodegeneration

新型伴侣和神经退行性疾病

基本信息

批准号：
10836715
负责人：
Kenneth Matthew Scaglione
金额：
$ 7.89万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10836715
关键词：
Alzheimer&apos s Disease Amyloid Amyotrophic Lateral Sclerosis Behavioral Binding Biochemical Biophysics Cell Aggregation Cells Data Development Dictyostelium Dictyostelium discoideum Disease Effectiveness Human Huntington Disease Huntington gene Induced pluripotent stem cell derived neurons Laboratories MJD1 protein Machado-Joseph Disease Mammalian Cell Modeling Molecular Molecular Chaperones Names Natural Resistance Nature Nerve Degeneration Neurodegenerative Disorders Neurons Organism Parkinson Disease Pathologic Pathway interactions Patients Phenotype Proteins Resistance Serine Therapeutic Therapeutic Effect Toxic effect Ubiquitin Work Zebrafish curative treatments disease phenotype induced pluripotent stem cell insight misfolded protein mouse model multicatalytic endopeptidase complex mutant neuron loss novel novel therapeutics polyglutamine prevent protective effect protein aggregation

项目摘要

Abstract The polyglutamine (polyQ) diseases are a class of nine neurodegenerative diseases caused by the expansion of a polyQ tract in specific proteins. Expansion of the polyQ tract results in protein aggregation and neurodegeneration. Currently there are no curative treatments for the polyQ diseases. One potential therapy for the polyQ diseases is the development of strategies to reduce polyQ aggregation. Interestingly we and others have found that one organism, Dictyostelium discoideum, is naturally resist to polyQ aggregation. Further work from our laboratory has identified a novel molecular chaperone we named serine rich chaperone protein 1 (SRCP1) that is both necessary for Dictyostelium’s resistance to polyQ aggregation and sufficient to impart resistance to polyQ aggregation to other organisms. In this application we propose to 1) determine the molecular mechanism SRCP1 utilizes to recognize polyQ expanded proteins and suppress their aggregation; 2) determine if SRCP1 can suppress protein aggregation and behavioral deficits in a mouse model of Huntington’s disease; and 3) determine if SRCP1 is capable of suppressing polyQ aggregation in a mouse model of Spinocerebellar ataxia type 3. Together these studies will determine the mechanism SRCP1 utilizes to suppress polyQ aggregation and determine if SRCP1 has the ability to prevent or reverse disease phenotypes in mouse models of polyQ disease. !

抽象的聚谷氨酰胺（polyq）疾病是由膨胀引起的九类神经退行性疾病的类别特定蛋白质中的polyq道。 polyq道的膨胀导致蛋白质聚集和神经变性。目前没有现代治疗PolyQ疾病。一种潜在的疗法 PolyQ疾病是减少PolyQ聚集的策略的发展。有趣的是，我们和他人已经发现，一种有机体，即dictyostelium discoideum，自然抗Polyq聚集。进一步的工作从我们的实验室确定了一种新型的分子链酮，我们将富含链链蛋白蛋白1命名（srcp1）既是dictyostelium对Polyq聚集的抗性又足够赋予的必要对PolyQ聚集对其他生物的抗性。在此应用中，我们建议1）确定分子机理SRCP1利用识别Polyq膨胀的蛋白质并抑制其聚集。 2）确定如果SRCP1可以抑制蛋白质聚集，并且行为在亨廷顿氏病小鼠模型中定义； 3）确定SRCP1是否能够抑制脊椎小鼠模型中的PolyQ聚集共济失调3型。这些研究将确定SRCP1的机理抑制Polyq 聚集并确定SRCP1在小鼠模型中是否具有预防或逆转疾病表型的能力 Polyq疾病。呢