Functional significance of PACAP in inhibiting neuronal cell death by using gene targeting method

PACAP基因打靶抑制神经细胞死亡的功能意义

• 批准号: 09558098
• 负责人: SHIODA Seiji
• 金额: $ 5.76万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09558098/
• 关键词: PACAP; Delayed neuronal cell death; Signal transduction; Transgenic mouse; 免疫組織化学; 遺伝子組織化学; マウス; ラット

We have demonstrated that the ischemia-induced apoptosis of neurons in the CA1 region of the rat hippocampus was prevented by either intracerebroventricular or intravenous infusion of pituitary adenylate cyclase-activating polypeptide (PACAP). However, the molecular mechanisms underlying the anti-apoptotic effect of PACAP remain to be determined. Within 3-6 h after ischemia, the activities of members of the mitogen-activated protein (MAP) kinase family, including extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), and p38 were increased in the hippocampus. The ischemic stress had a potent influence on the MAP kinase family, especially on JNK/SAPK. PACAP inhibited the activation of JNK/SAPK after ischemic stress. These suggest that PACAP acts to inhibit the JNK/SAPK signaling pathway, thereby protecting neurons against apoptosis. We have recently succeeded to make PACAP receptor transgenic mice, therefore we are now trying to clarify direct effect of PACAP on inhibiting neuronal cell death via its specific receptors.

我们已经证明，脑室内或静脉输注垂体腺苷酸环化酶激活多肽（PACAP）可以防止缺血诱导的大鼠海马 CA1 区神经元细胞凋亡。然而，PACAP 抗凋亡作用的分子机制仍有待确定。缺血后3-6小时内，海马中丝裂原激活蛋白（MAP）激酶家族成员的活性增加，包括细胞外信号调节激酶（ERK）、Jun N末端激酶（JNK）/应激激活蛋白激酶（SAPK）和p38。缺血应激对 MAP 激酶家族，尤其是 JNK/SAPK 具有强大的影响。 PACAP 抑制缺血应激后 JNK/SAPK 的激活。这些表明 PACAP 可以抑制 JNK/SAPK 信号通路，从而保护神经元免于凋亡。我们最近成功制作了PACAP受体转基因小鼠，因此我们现在试图阐明PACAP通过其特异性受体抑制神经元细胞死亡的直接作用。

项目成果

K. Ito: "Bioluminescent enzyme immunoassay for pituitary adenylate cyclase activating polypeptide 38(PAACAP38)"Analytica Chimica Acta. 382. 245-251 (1999)

K. Ito：“垂体腺苷酸环化酶激活多肽 38 (PAACAP38) 的生物发光酶免疫测定”Analytica Chimica Acta。

Funahashi H, Yada T, Muroya S, Takigawa M, Ryushi T, Horie S, Nakai Y, Shioda S: "The effect of leptin on feeding-regulating neurons in the hypothalamus."Neurosci Lett. 264. 117-120 (1999)

Funahashi H、Yada T、Muroya S、Takikawa M、Ryushi T、Horie S、Nakai Y、Shioda S：“瘦素对下丘脑摄食调节神经元的影响。”Neurosci Lett。

Zhou, C-J, Kikuyama S, Shibanuma M, Arimura A, Shioda S: "Cellular distribution of the splice variants of the receptor for pituitary adenylate cyclase-activating polypeptide (PACI-R ) in the rat brain by in situ RT-PCR"Mol Brain Res. 95. 150-158 (2000)

Zhou，C-J，Kikuyama S，Shibanuma M，Arimura A，Shioda S：“通过原位 RT-PCR 观察大鼠脑中垂体腺苷酸环化酶激活多肽 (PACI-R) 受体剪接变体的细胞分布”Mol

K.Ito: "Bioluminescent enzyme immunoassay for pituitary adenylate cyclase activating polypeptide 38(PACAP38)"Analytica Chimica Acta. 382. 245-251 (1999)

K.Ito：“垂体腺苷酸环化酶激活多肽 38（PACAP38）的生物发光酶免疫测定”Analytica Chimica Acta。

S,Shioda: "PACAP protects hippocampal neurons against apoptosis.Involvement of JNK/SAPK signaling pathway" Ann.N.Y.Acad.Sci.865. 111-117 (1998)

S，Shioda：“PACAP 保护海马神经元免受细胞凋亡。JNK/SAPK 信号通路的参与”Ann.N.Y.Acad.Sci.865。