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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 神经退行性疾病的一个基本特征是泛素化蛋白在神经元包涵体中的积累和聚集，例如阿尔茨海默病中的神经元缠结帕金森氏病与路易体s病（PD）。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。本申请的主要目的是表征 在与炎症相关的应激条件下，泛素化蛋白在神经元细胞中积累和聚集，并防止蛋白聚集以潜在地阻碍细胞死亡。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（PGJ 2）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，如炎症的神经毒性产物PGJ 2诱导的应激条件下，多聚泛素化蛋白被螯合成聚集体，防止其降解并促进细胞死亡。我们希望，在压力条件下积累的多聚泛素化蛋白质的表征将提供线索，聚集生物合成。(2)确定在特定目标1中鉴定的多聚泛素化蛋白在死后人脑组织中被检测到。我们提出，在特定目标1中鉴定的聚泛素化蛋白，在PGJ 2处理后在SK-N-SH细胞中积累和聚集，也将在与神经变性相关的应激条件下在人脑中积累和聚集。(3)检查药理学策略的潜力，以防止PGJ 2处理后在应激的人SK-N-SH神经母细胞瘤细胞中观察到的泛素化蛋白质聚集和活力丧失。我们建议，预防多聚泛素化蛋白的聚集将促进其降解，伴随着神经元细胞的存活。总的来说，我们期望，对在应激神经元细胞中积累和聚集的多聚泛素化蛋白的表征将提供对神经元包涵体生物发生的深入了解，并强调发现用于治疗干预的新靶点以防止与神经变性相关的蛋白质聚集的潜力，以及开发与应激神经元细胞中泛素化蛋白积累相关的神经变性疾病风险个体的标记物的潜力。神经元包涵体，如AD和PD。