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

Development of a self-regulated neuroprotective gene therapy for Parkinsons Disease and other synucleinopathies

开发针对帕金森病和其他突触核蛋白病的自我调节神经保护基因疗法

基本信息

批准号：
9809188
负责人：
ROBERT E GROSS
金额：
$ 42.54万
依托单位：
EMORY 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：
2019-09-06 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9809188
关键词：
Address Adverse effects Affect Aging Amyloid beta-Protein Area Autophagocytosis Behavior Biological Brain region Cell Death Cell Line Cell model Cellular Stress Chemicals Degradation Pathway Dementia Development Disease Dose Early Intervention Event Exposure to Feedback Gene Delivery Image Analysis Intervention Kinetics Lead Lesion Lewy Body Dementia Link Methods Molecular Molecular Neurobiology Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Outcome Parkinson Disease Parkinson&apos s Dementia Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Process Protein Degradation Induction Proteins RNA Regulation Reporter Role Signal Transduction Specificity Technology Testing Therapeutic Time Translations activating transcription factor 4 alpha synuclein brain cell design disabling symptom dosage drug discovery gene therapy high throughput screening innovation live cell imaging misfolded protein neuroprotection neurotoxic prevent protein degradation protein misfolding proteostasis response synthetic biology synucleinopathy targeted treatment tau Proteins tool

项目摘要

α-Synucleinopathies are neurodegenerative diseases characterized by intracellular inclusions of α-synuclein (α- syn) aggregates and they include conditions such as Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). A prevailing view is that disease-associated factors such as aging compromise the ability of neurons to efficiently clear abnormally folded proteins which leads to the formation of intracellular aggregates and neurodegeneration. While enhancing the clearance of misfolded α-syn is a potential therapeutic strategy for PD, current methods to activate cellular mechanisms for protein degradation rely mostly on pharmacological inducers or conventional gene delivery interventions. A translational roadblock in these approaches is the lack of control over dosage, precise time of intervention, and undesirable effects associated with the broad and sustained modulation of cellular degradation pathways. To address these therapeutic needs, we propose to develop a responsive gene therapy for the self-sufficient delivery of a neuroprotective therapy targeting the clearance of misfolded α-syn species. In a cellular model of α-syn seeded aggregation, we will demonstrate that our gene therapy approach can detect biological responses associated with the accumulation of α-syn (Aim 1) and respond by modulating protein degradation pathways accordingly (Aim 2). We expect the outcomes of this project to enable a strategy where a therapy is produced as needed by the affected brain regions, opening the possibility to intervene at an early stage for the treatment of otherwise intractable neurodegenerative conditions such as PD. This project has the potential to be transformative as it introduces a modular platform technology with translational potential for other neurological targets linked to the neurotoxic behavior of misfolded proteins (e.g. amyloid-β, tau).

α-突触核蛋白病是以细胞内α-突触核蛋白（α-）包涵为特征的神经退行性疾病