PLASMALOPSYCHOSINE AS NEUROTROPHIC FACTOR

作为神经营养因子的缩醛磷脂

• 批准号: 6499452
• 负责人: Sen-itiroh Hakomori
• 金额: $ 30.25万
• 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/6499452
• 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（逐字摘自申请人摘要）：脂肪醛 缀合物以前限于磷脂形式， 缩醛磷脂我们最近发现了一种新的等离子体共轭物， 半乳糖基鞘氨醇（psychosine）或通过环缩醛转化为糖苷 连接;这些被称为“plasmalopsychosine”（PLPS）， “血浆脑苷脂”（PLCER）。PLPS诱导神经营养和 通过TrkA激活和延长的抗PC 12细胞凋亡作用 促分裂原活化蛋白激酶的增强。PLPS诱导类似的效应 在神经母细胞瘤Neuro 2a细胞中，独立于神经生长的影响 因子（NGF）。因此，PLPS模拟NGF作用。我们建议研究：（1）结构 PLPS的神经营养和抗凋亡作用的要求;（2）可能的 PLCER向PLPS的酶促转化，以及PLPS的组织分布模式 PLPS和PLCER的神经营养作用;（3）PLPS的神经营养作用与已知的 各种神经元细胞系中的神经营养因子;（4）PLPS与 神经营养因子受体和“糖信号传导结构域”（GSD）， TrkA、p75 NTR和其他GSD相关信号转导物的激活;（5） PLPS对正常原代培养神经元的抗凋亡活性，（6） 参与PLPS抗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，p38 MAPK，AW PBK 3，pS3肿瘤抑制基因， Bc 1 -2家族（Bc 1 -2，BC 1-XL，Bax，Bad），半胱天冬酶，[Ca 2 +];自由基 生产和线粒体功能。这些研究的结果可以提供 为开发PLPS及其类似物作为治疗试剂的基础， 神经变性疾病和神经元损伤。