NEUROSCI RES: PROJ2:PARKINSON'S DISEASE:CYSTATIN C REGULATES CELL DEATH

神经科学研究：项目 2：帕金森病：细胞周期抑制剂 C 调节细胞死亡

• 批准号: 7561439
• 负责人: DONALD E PALM
• 金额: $ 5.72万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561439
• 关键词: Aging; Apoptosis; Aspartic Endopeptidases; Biochemical; Cathepsins; Cathepsins B; Cell Death; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Cultured Cells; Cystatins; Cysteine Protease; Disease; Disease model; Endopeptidases; Event; Funding; Grant; In Vitro; Injection of therapeutic agent; Injury; Institution; Messenger RNA; Nerve Degeneration; Neuronal Injury; Neurons; Oxidopamine; PC12 Cells; Parkinson Disease; Pathway interactions; Peptide Hydrolases; Proteins; Rattus; Research; Research Personnel; Resources; Role; Source; Substantia nigra structure; Testing; Toxic effect; United States National Institutes of Health; dopaminergic neuron; enzyme activity; in vivo; inhibitor/antagonist; injured; post gamma-globulins; research study

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. Suppression of the lysosomal cysteine proteases have been identified in aging and various types of neuronal injuries. However, the role of the lysosomal proteases has not been investigated in Parkinson¿s Disease (PD). Recent in vitro studies have demonstrated an alternate programmed cell death pathway due to specific inhibition of cathepsin B resulting in an increased activity of the aspartate protease cathepsin D. Cystatin C is a potent endogenous inhibitor of the lysosomal cysteine proteases and has been identified in degenerating neurons with immunohistochemical analysis following injury. The objective of this project is to elucidate the potential relationship of cystatin C with the cysteine protease cathepsin B, and the aspartate protease cathepsin D using the experimental PD model of 6-hyroxydopamine toxicity. Thus, the proposed experiments examine and test the hypothesis that cystatin C contributes to cathepsin D induced neurodegeneration by suppressing cathepsin B in the dopaminergic neurons following 6-hydroxydopamine injection. This hypothesis will be tested in vitro with PC-12 cell cultures exposed to 6-hydroxydopamine toxicity and in vivo with 6-hydroxydopamine injections into the substantia nigra of rats. Co-localization of cystatin C with cathepsins B and D as well as quantitative changes in protein and messenger RNA and enzyme activity will be determined in injured neurons and PC-12 cells undergoing apoptosis. These findings are expected to increase the understanding of the complex cascade of biochemical events that ultimately leads to neuronal degeneration in PD.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 在衰老和各种类型的神经元损伤中已经确定了溶酶体半胱氨酸蛋白酶的抑制。然而，在帕金森病（PD）中尚未研究溶酶体蛋白酶的作用。最近的体外研究表明，由于组织蛋白酶B的特异性抑制作用导致天冬氨酸蛋白质蛋白酶D. Cystatin C的活性增加，这是一种替代的程序性细胞死亡途径，Cystatin C是溶酶体半胱氨酸蛋白的潜在内源性抑制剂，并在脱发神经元进行了免疫组织治疗术中鉴定出来。该项目的目的是使用6-羟基多巴胺毒性的实验性PD模型阐明半胱氨酸C与半胱氨酸蛋白结蛋蛋白B的潜在关系以及天冬氨酸蛋白质蛋白酶D。这是拟议的实验检查和检验的假设，即伴半胱氨酸蛋白酶C在6-羟基多巴胺注射后通过抑制多巴胺能神经元中的组织蛋白蛋白蛋白蛋白蛋白蛋白蛋白B，导致组织蛋白酶诱导神经退行性。该假设将在体外用PC-12细胞培养物暴露于6-羟基多巴胺的毒性和体内，并在体内对大鼠的黑质进行了6-羟基多巴胺注射。与组织蛋白酶B和D共定位Cystatin C以及蛋白质和信使RNA和酶活性的定量变化将在受伤的神经元和正在凋亡的PC-12细胞中确定。这些发现有望增加对最终导致PD神经元变性的复杂级联反应的理解。