BIOINFORMATICS ANALYSIS OF NEURODEGENERATIVE PATHWAYS

神经退行性通路的生物信息学分析

• 批准号: 7336012
• 负责人: MARIA Emilia FIGUEIREDO-PEREIRA
• 金额: $ 15.04万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336012
• 关键词: BIOINFORMATICS; ANALYSIS; NEURODEGENERATIVE; PATHWAYS

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 Alzheimer¿s disease (AD) and Lewy bodies in Parkinson¿s 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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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聚集和聚集，如阿尔茨海默病(AD)中的神经原纤维缠结(AD)和帕金森S病(PD)中的路易小体。神经元包涵体中聚集的大多数泛素化蛋白的特性及其在神经退行性变过程中的作用尚不清楚。这项应用的主要目的是表征在与炎症相关的应激条件下在神经细胞中积累和聚集的泛素化蛋白质，并防止蛋白质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)利用蛋白质组学方法鉴定前列腺素J2(PGJ2)处理的SK-N-SH神经母细胞瘤细胞中聚集和聚集的泛素化蛋白。我们认为，在应激条件下，如炎症的神经毒性产物PGJ2诱导的条件下，多泛素蛋白被隔离在聚集体中，防止它们的降解并促进细胞死亡。我们期望对在胁迫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)确定在特定目的1中发现的多泛素化蛋白在死后的人脑组织中被检测到。我们认为，在特定目标1中发现的多泛素化蛋白，经PGJ2处理后，在SK-N-SH细胞中积累和聚集，在与神经退化相关的应激条件下，也将在人脑中积累和聚集。(3)研究药物策略的可能性，以防止在PGJ2处理时观察到的应激人SK-N-SH神经母细胞瘤细胞泛素化蛋白的聚集和活力丧失。我们认为，阻止多泛素化蛋白的聚集将促进它们的降解，并伴随着神经细胞的存活。总体而言，我们预计，对在应激神经细胞中积累和聚集的泛素化蛋白的表征将为神经元包涵体的生物发生提供洞察力，并强调发现新的治疗干预靶点的潜力，以防止与神经退行性变相关的蛋白质聚集，并为与泛素化蛋白在神经元包涵体中积累相关的神经退行性疾病风险个体开发标记，如AD和PD。