权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Fluorescent IRE sensor for PD drug discovery

用于 PD 药物发现的荧光 IRE 传感器

基本信息

批准号：
9554287
负责人：
Carolyn Carr
金额：
$ 22.19万
依托单位：
LUCERNA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2020-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9554287
关键词：
5&apos Untranslated Regions Adopted Affect Affinity Age Animal Model Binding Biological Assay Broccoli - dietary Buffers Bypass Cell Line Cessation of life Disease Distal Drug Interactions Drug Monitoring Drug Screening Drug Targeting Elements Event Exhibits Ferritin Fluorescence Frequencies Gene Dosage Gene Expression Genetic study Goals Guidelines In Vitro Iron Lead Length Lewy Bodies Ligands Link Luciferases Mediating Messenger RNA Methods Molecular Conformation Morphologic artifacts Motor Nature Neurodegenerative Disorders Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Performance Pharmaceutical Preparations Phase Play Population Positioning Attribute Protein Biosynthesis Protein Synthesis Inhibitors Proteins RNA Reporter Role SNCA gene Severity of illness Signal Transduction Small Business Innovation Research Grant Specificity Structure Substantia nigra structure System Technology Time Transducers Translational Research Translations Validation alpha synuclein assay development base commercialization dopaminergic neuron drug discovery effective therapy fluorophore high throughput screening inhibitor/antagonist knock-down novel overexpression presynaptic prevent protein aggregate protein expression sensor small molecule stem synuclein therapeutic target

项目摘要

SUMMARY Parkinson's disease (PD) is a debilitating neurodegenerative disease that affects about 1-2% of the population over the age of 60. The pathological hallmark of PD is the presence of intracellular protein aggregates that cause the degeneration and then death of dopaminergic neurons in the substantia nigra. The presynaptic protein α-synuclein was found to be the main component of Lewy bodies and α-synuclein aggregation is believed to be the key event in PD pathogenesis. Past drug discovery efforts have been focused on preventing α-synuclein aggregation or increasing α-synuclein clearance. However, overexpression and knockdown studies in cell lines and animal models showed that altering intracellular α-synuclein protein levels can also regulate PD pathology. These results suggest that α-synuclein translation is a significant yet under explored target for PD drug discovery. A putative iron-responsive element (IRE) that exhibited high sequence and structural similarities with the ferritin IRE was found in the distal 5'-untranslated region of α-synuclein mRNA and studies suggest that this IRE plays a critical role in regulating α-synuclein translation. Thus far, there is no high-throughput drug discovery methods that can interrogate drug binding directly to RNA structures that control protein translation. This is needed to bypass artifact-prone protein reporters that are typically used to study translation inhibitors. Therefore, this phase I SBIR application aims to develop a fluorescence sensor that monitors drug binding to IREs and can enable high-throughput drug screens for compounds that specifically target α-synuclein's IRE and ultimately result in lead compounds that could eventually be developed into inhibitor of α-synuclein protein synthesis.

总结