PLASMALOPSYCHOSINE AS NEUROTROPHIC FACTOR

作为神经营养因子的缩醛磷脂

• 批准号: 6040911
• 负责人: Sen-itiroh Hakomori
• 金额: $ 30.39万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-04 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6040911
• 关键词: BCL2 gene /protein; JUN kinase; apoptosis; biological signal transduction; cell growth regulation; cell line; cerebrosides; chemical conjugate; free radicals; glycosphingolipids; growth factor receptors; laboratory rat; mitochondria; mitogen activated protein kinase; neurons; neurotrophic factors; protein localization; sphingosine; tissue /cell culture

DESCRIPTION ( verbatim from the applicant's abstract): Fatty aldehyde conjugates have been limited previously to phospholipids in the form of plasmalogen. We recently found a novel plasmal conjugate linked to galactosyl-sphingosine (psychosine) or to cerebroside through cyclic acetal linkage; these were termed "plasmalopsychosine" (PLPS) and "plasmalocerebroside'' (PLCER), respectively. PLPS induces neurotrophic arid anti-apoptotic effects in PC 12 cells through TrkA activation and prolonged enhancement of mitogen-activated protein kinase. PLPS induces similar effects in neuroblastoma Neuro2a cells independent from the effect of Nerve Growth Factor (NGF). Thus, PLPS mimics NGF effect. We propose to study: (1) structural requirements for neurotrophic and anti-apoptotic effects of PLPS; (2) possible enzymatic conversion of PLCER to PLPS, and tissue distribution pattern of PLPS and PLCER; (3) comparison of neurotrophic effects of PLPS with effects of known neurotrophins in various neuronal cell lines; (4) interactions of PLPS with neurotrophin receptors and "glycosignaling domain" (GSD) which lead to activation of TrkA, p75NTR and other GSD-associated signal transducers; (5) anti-apoptotic activity of PLPS for normal, primary cultured neurons, (6) signal transduction pathways involved in the anti-apoptotic action of PLPS in cultured central and peripheral nervous system neurons, including kinase pathways (ERK, JNK, p38MAPK, AW PBK3, the pS3 tumor suppressor gene, members of the Bc1-2 family (Bc1-2, BC1-XL, Bax, Bad), caspases, [Ca2+]; free radical production and the mitochondrial function. Results of these studies may provide a basis for development of PLPS and its analogues as therapeutic reagents for neurodegenerative diseases and neuronal injury.

描述(逐字摘自申请者摘要)：脂肪醛 偶联物以前仅限于磷脂，其形式为 纤溶酶原。我们最近发现了一种新的与 半乳糖-鞘氨醇(神经素)或通过环缩醛转化为脑苷脂 连接；这些被称为“血浆脑脊液”(PLPS)和 “血浆脑苷‘’(PLCER)。PLPS诱导神经营养和 TrkA激活并延长对PC-12细胞的抗凋亡作用 丝裂原活化蛋白激酶的增强。PLP引起类似的影响 神经母细胞瘤中不受神经生长影响的Neuro2a细胞 因子(NGF)。因此，PLPS模拟了NGF效应。我们建议研究：(1)结构 PLPS的神经营养和抗细胞凋亡作用的要求；(2)可能 PLCER酶转化为PLPS及PLPS的组织分布 和PLCER；(3)PLPS的神经营养作用与已知作用的比较 不同神经细胞系中的神经营养因子；(4)PLPS与神经营养因子的相互作用 神经营养素受体和糖信号结构域(GSD)导致 激活TrkA、p75NTR和其他与GSD相关的信号转导；(5) PLPS对正常原代培养神经元的抗凋亡作用(6) PLPS抗细胞凋亡作用的信号转导途径 培养的中枢和外周神经系统神经元，包括激酶 途径(ERK，JNK，p38MAPK，AW PBK3，PS3抑癌基因，成员 Bc1-2家族(Bc1-2、Bc1-xl、Bax、Bad)、caspase、[Ca~(2+)]；自由基 生产和线粒体功能。这些研究的结果可能会提供 PLPS及其类似物作为血吸虫病治疗试剂的开发基础 神经退行性疾病和神经元损伤。