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（逐字从申请人的摘要中）：脂肪醛 以前以前限制了以磷脂的形式 血浆原。我们最近发现了一种与 半乳糖基 - 肾上腺素（Psychosine）或通过循环乙酰乙酸盐 连锁;这些被称为“静脉假体”（PLP）和 “浆膜尿素”（PLCER）分别。PLPS诱导神经营养干旱 通过TRKA激活，PC 12细胞中的抗凋亡效应并延长 促分裂原激活蛋白激酶的增强。 PLP诱导类似的效果 在神经母细胞瘤神经2a细胞中，独立于神经生长的作用 因子（NGF）。因此，PLP模拟NGF效应。我们建议研究：（1）结构 PLP的神经营养和抗凋亡作用的要求； （2）可能 PLCer酶促转化为PLP和PLP的组织分布模式 和plcer; （3）PLP的神经营养作用与已知的作用的比较 各种神经元细胞系中的神经营养蛋白； （4）PLP与 神经营养蛋白受体和“糖质信号结构域”（GSD）导致 TRKA，P75NTR和其他GSD相关信号传感器的激活； （5） PLP的抗凋亡活性对于正常的原发性培养神经元，（6） PLP的抗凋亡作用涉及的信号转导途径 培养的中枢和周围神经系统神经元，包括激酶 途径（ERK，JNK，P38MAPK，AW PBK3，PS3肿瘤抑制基因，成员 BC1-2家族（BC1-2，BC1-XL，BAX，BAX），caspase，[Ca2+];自由基 生产和线粒体功能。这些研究的结果可能会提供 开发PLP及其类似物作为治疗试剂的基础 神经退行性疾病和神经元损伤。