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) 在细胞内选择性降解中发挥核心作用 蛋白质。我们提出的转化研究涉及 UPP 监管机制，这些机制可以 操纵以增加中枢神经系统损伤后的神经保护和/或神经元恢复。有一个 对这些 UPP 调节机制的了解存在明显差距。该应用程序的主要目标是 描述 UPP 调节的神经保护和促进神经突的分子机制 中枢神经系统损伤后的生长产物。为了表征这些 UPP 调节途径，UPP 步骤中的两个是 操纵：（1）通过药理学和更具体的遗传方法进行蛋白酶体活性和 (2) 通过过度表达泛素连接酶来泛素化，促进神经突生长。这些效果 UPP 操作将在人神经母细胞瘤 SK-N-SH 细胞以及大鼠背根中进行研究 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， 通过生化和免疫细胞化学分析，我们将评估 UPP 操作对 小 GTP 酶的 Rho 家族，关于产生腐胺的酶鸟氨酸脱羧酶 (ODC)，以及 神经元特异性泛素水解酶 UCH-L1 的表达。我们的工作假设是 UPP 操纵 将 (1) 影响 Rho 蛋白的水平，进而增强神经突的生长，如 Rho 蛋白质是防止中枢神经系统神经突生长和轴突再生的关键因素，(2) 增强 ODC 导致腐胺水平升高，进而阻止髓鞘质抑制剂对神经突生长的影响， (3) 改变 UCH-L1 的水平，从而促进泛素分子的使用和再利用，这一过程 将调节与中枢神经系统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 UPP (Figueiredo-Pereira) 团队的独特技能和专业知识组合， 轴突再生（Filbin）。我们希望我们的结果适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：我们的研究涉及可被操纵以增加 中风、脊髓损伤等神经系统疾病后的神经保护和/或神经元恢复！ 和阿尔茨海默病。它与健康差异尤其相关，例如非洲裔美国人： 西班牙裔和西班牙裔的中风死亡率均高于美国白人。老化： 非裔美国人和西班牙裔人口提出了一个特殊的挑战，因为老年人 患有中风的人患阿尔茨海默病等神经退行性疾病的风险较高。 预计我们的转化研究将确定有效治疗中枢神经系统损伤的新靶点。