SNRP at Hunter College

亨特学院 SNRP

• 批准号: 7349987
• 负责人: MARIA Emilia FIGUEIREDO-PEREIRA
• 金额: $ 26.6万
• 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: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349987
• 关键词: Alzheimer' s disease; axon; conditioning; dendrites; injury; neurons; neuroprotectants; proteins; putrescine; regeneration; spinal cord injury; stroke; ubiquitin; university

The ubiquitin/proteasome pathway (UPP) plays a central role in the selective degradation of intracellular proteins. The translational research that we propose addresses UPP-regulated mechanisms that can be manipulated to increase neuroprotection and/or neuronal recovery following CNS injuries. There is an obvious gap in the knowledge of these UPP-regulated mechanisms. The main goal of this application is to characterize molecular mechanisms regulated by the UPP that are neuroprotective and promote neurite outgrowth following CNS injury. To characterize these UPP-regulated pathways, two of the UPP steps will be manipulated: (1) Proteasorne activity by pharmacological and more specific genetic approaches and (2) Ubiquitination by overexpressing a ubiquitin ligase that promotes neurite outgrowth. The effect of these UPP manipulations will be investigated in human neuroblastoma SK-N-SH cells as well as in rat dorsal root ganglion and cortical neurons grown in the presence of axonal regeneration inhibitors. Through molecular, biochemicaland immunocytochemical analyses we will assess the effects of the UPP-manipulations on the Rho family of small GTPases, on the putrescine-producing enzyme ornithine decarboxylase (ODC), and on the expression of the neuron-specific ubiquitin hydrolase, UCH-L1. Our working hypothesis is that the UPP-manipulations will (1) affect the levels of Rho proteins, which will in turn enhance neurite outgrowth, as Rho proteins are key players in preventing CNS neurite outgrowth and axonal regeneration, (2) enhance ODC levels causing a rise in putrescine, which in turn will block the effect of myelin inhibitors on neurite outgrowth, and (3) alter the levels of UCH-L1, which facilitates the use and reuse of ubiquitin molecules, a process that will regulate the turnover of proteins relevant to CNS neurite outgrowth and axonal regeneration. This project draws on the unique combination of skills and expertise of our groups on the UPP (Figueiredo-Pereira) and axonal regeneration (Filbin). We expect our results to be applicable to treatment-of neurological conditions that involve neuronal damage, such as stroke, neurodegenerative disorders and spinal cord injury. Relevance to Public Health: Our research addresses mechanisms that can be manipulated to increase neuroprotection and/or neuronal recovery following neurological conditions such as stroke, spinal cord injury! and Alzheimer's disease. It is particularly relevant to health disparities as, for example, African-Americans: and Hispanics of both genders have a higher death rate due to stroke than White Americans. The aging: population of African-Americans and Hispanics presents a particular challenge, as older adults who havei had a stroke have a higher risk of developing neurodegenerative disorders such as Alzheimer's disease. expect that our translational research will identify new targets for effectively treating CNS injury.

泛素/蛋白酶体途径（UPP）在细胞内蛋白质的选择性降解中起着重要作用。 proteins.我们提出的转化研究解决了UPP调节机制， 以增加CNS损伤后的神经保护和/或神经元恢复。有一个 这些UPP调节机制的知识存在明显差距。此应用程序的主要目标是 表征由UPP调节的神经保护和促进神经突的分子机制 CNS损伤后的生长。为了表征这些UPP调节的途径，将进行两个UPP步骤， 操作：（1）通过药理学和更具体的遗传方法的蛋白酶活性， (2)通过过表达泛素连接酶促进神经突生长的泛素化。这些的作用 将在人神经母细胞瘤SK-N-SH细胞以及大鼠背根中研究UPP操作 在轴突再生抑制剂存在下生长的神经节和皮质神经元。通过分子， 通过生物化学和免疫细胞化学分析，我们将评估UPP操作对 Rho家族的小GTP酶，对腐胺产生酶鸟氨酸脱羧酶（ODC），以及对 神经元特异性泛素水解酶UCH-L1的表达。我们的工作假设是， 将（1）影响Rho蛋白的水平，这反过来又会促进神经突的生长，因为Rho 蛋白质是阻止CNS神经突生长和轴突再生的关键角色，（2）增强ODC 导致腐胺升高的水平，这反过来又会阻止髓鞘抑制剂对神经突生长的影响， 和（3）改变UCH-L1的水平，这有利于泛素分子的使用和再利用，这一过程 将调节与CNS神经突生长和轴突再生相关的蛋白质的周转。这个项目 利用我们在UPP（Figueiredo-Pereira）小组的独特技能和专业知识， 轴突再生（Filbin）。我们希望我们的研究结果能应用于神经系统疾病的治疗 涉及神经元损伤，如中风、神经退行性疾病和脊髓损伤。 与公共卫生的相关性：我们的研究涉及可以操纵以增加 神经保护和/或神经元恢复后的神经病症，如中风，脊髓损伤！ 和老年痴呆症这与健康差距特别相关，例如，非洲裔美国人： 西班牙裔男女的中风死亡率都高于白色美国人。老化： 非洲裔美国人和西班牙裔美国人的人口提出了一个特殊的挑战，因为老年人谁拥有 中风的人患神经退行性疾病如阿尔茨海默病的风险更高。 我们希望我们的转化研究能为有效治疗CNS损伤找到新的靶点。