BIOINFORMATICS ANALYSIS OF NEURODEGENERATIVE PATHWAYS

神经退行性通路的生物信息学分析

• 批准号: 7561517
• 负责人: MARIA Emilia FIGUEIREDO-PEREIRA
• 金额: $ 17.11万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561517
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Alzheimer' s Disease; Autopsy; Biogenesis; Bioinformatics; Brain; Cell Death; Cells; Characteristics; Computer Retrieval of Information on Scientific Projects Database; Condition; Development; Funding; Grant; Human; Individual; Inflammation; Institution; Lewy Bodies; Link; Nerve Degeneration; Neuroblastoma; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parkinson Disease; Pathway interactions; Prevention; Proteins; Proteomics; Research; Research Personnel; Resources; Risk; Role; Source; Stress; Therapeutic Intervention; United States National Institutes of Health; brain tissue; insight; neuronal survival; neurotoxic; prevent; protein aggregation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A fundamental characteristic of neurodegenerative disorders is the accumulation and aggregation of ubiquitinated proteins in neuronal inclusions, such as neurofibrillary tangles in Alzheimers disease (AD) and Lewy bodies in Parkinsons disease (PD). The identity of most ubiquitinated proteins that accumulate in neuronal inclusions and their role in the progression of neurodegeneration are unknown. The main objectives of this application are to characterize ubiquitinated proteins that accumulate and aggregate in neuronal cells under stress conditions associated with inflammation and to prevent protein aggregation to potentially hinder cell death. To accomplish our main objectives the following three specific aims are proposed: (1) Identify ubiquitinated proteins that accumulate and aggregate in prostaglandin J2 (PGJ2)-treated human SK-N-SH neuroblastoma cells using a proteomics approach. We propose that under stress conditions such as those induced by PGJ2, a neurotoxic product of inflammation, the sequestration of polyubiquitinated proteins into aggregates prevents their degradation and promotes cell death. We expect that characterization of polyubiquitinated proteins that accumulate under stress conditions will provide clues to aggregate biogenesis. (2) Establish that the polyubiquitinated proteins identified in specific aim 1 are detected in postmortem human brain tissue. We propose that polyubiquitinated proteins identified in specific aim 1, shown to accumulate and aggregate in SK-N-SH cells upon PGJ2-treatment, will also accumulate and aggregate in human brain under stress conditions associated with neurodegeneration. (3) Examine the potential of pharmacological strategies to prevent the aggregation of ubiquitinated proteins and loss of viability observed in stressed human SK-N-SH neuroblastoma cells upon PGJ2-treatment. We propose that prevention of the aggregation of polyubiquitinated proteins will promote their degradation with a concomitant survival of the neuronal cells. Overall, we expect that the characterization of polyubiquitinated proteins that accumulate and aggregate in stressed neuronal cells will provide insights into neuronal inclusion biogenesis and underscores the potential for the discovery of new targets for therapeutic intervention to prevent protein aggregation linked to neurodegeneration and the development of markers for individuals at risk for neurodegenerative disorders associated with the accumulation of ubiquitinated proteins in neuronal inclusions, such as AD and PD.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 神经退行性疾病的一个基本特征是神经元包涵体中泛素化蛋白的积累和聚集，例如阿尔茨海默病（AD）中的神经原纤维缠结和帕金森病（PD）中的路易体。大多数在神经元包涵体中积累的泛素化蛋白的身份及其在神经变性进展中的作用尚不清楚。该应用程序的主要目标是表征 泛素化蛋白质在与炎症相关的应激条件下在神经元细胞中积累和聚集，并防止蛋白质聚集，从而可能阻碍细胞死亡。为了实现我们的主要目标，提出了以下三个具体目标：（1）使用蛋白质组学方法鉴定前列腺素 J2（PGJ2）处理的人 SK-N-SH 神经母细胞瘤细胞中积累和聚集的泛素化蛋白。我们提出，在应激条件下，例如 PGJ2（一种炎症的神经毒性产物）诱导的应激条件下，多泛素化蛋白被隔离成聚集体，防止其降解并促进细胞死亡。我们期望在应激条件下积累的多泛素化蛋白的表征将为聚集生物发生提供线索。 (2) 确定在死后的人脑组织中检测到特定目标 1 中鉴定的多泛素化蛋白。我们提出，在特定目标 1 中鉴定的多泛素化蛋白在 PGJ2 治疗后会在 SK-N-SH 细胞中积累和聚集，在与神经退行性变相关的应激条件下也会在人脑中积累和聚集。 (3) 检查药物策略的潜力，以防止在 PGJ2 处理后应激的人 SK-N-SH 神经母细胞瘤细胞中观察到的泛素化蛋白聚集和活力丧失。我们认为，防止多泛素化蛋白的聚集将促进其降解，并伴随神经元细胞的存活。总体而言，我们期望对应激神经元细胞中积累和聚集的多泛素化蛋白的表征将为神经元包涵体生物发生提供见解，并强调发现治疗干预新靶点的潜力，以防止与神经变性相关的蛋白质聚集和标记物的开发适用于有神经退行性疾病风险的个体，这些疾病与神经元包涵体中泛素化蛋白的积累有关，例如 AD 和 PD。