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Molecular pathology of neuronal differentiation, migration and death in developmental disorders.

发育障碍中神经元分化、迁移和死亡的分子病理学。

基本信息

批准号：
08670933
负责人：
MIZUGUCHI Masashi
金额：
$ 1.6万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670933/
关键词：
Bak Tuberous sclerosis Miller-Dieker syndrome Apoptosis Tuberin PAF PAF acetylhydrolase

项目摘要

A.Neuronal deathWe produced a polyclonal antibody against Bak, a protein promoting neuronal apoptosis, and thereby studied its expression in human brains by Western blotting and immunostaining. In 1996, we investigated the changes associated with development and aging, and demonstrated that the expression of Bak is high in the fetal and aged brains. In 1997, we comapared Bak immunoreactivity between Down syndrome and control patients. In Down syndrome brains, the aging-related upregulation of Bak occurred prematurely. Cerebral neurons became Bak-positive prior to the development of neurofibrillary changes.B.Neuronal differentiationWe produced rabbit antibodies against the N-and C-terminal of tuberin, the product of the TSC2 gene responsible for tuberous sclerosis. In 1996, we demonstrated the expression of tuberin in control cerebra. During development, tuberin content increased with age. Tuberous sclerosis brains by contrast showed loss of tuberin, which was severe in both the hamartomatous lesions (cortical tuber and subependymal giant cell tumor) and histologically normal cortices. Tuberin immunoreactivity was also lost from the renal and cardiac hamartomas. In 1997, we observed a normal level of tuberin expression in focal cortical dysplasia, thereby indicating pathophysiological difference between tuberous sclerosis and cortical dysplasia.C.Neuronal migrationWe extended immunohistochemical studies of the LIS1 gene product (a 45k subunit of PAF acetylhydrolase), the defect of which being responsible for the Miller-Dieker lissencephaly syndrome. In 1996, we studied the expression of LIS1 in various migration disorders, and demonstrated that the loss of LIS1 is specific to the syndrome. In 1997, we immunostained human fetal brains and observed strong labeling of the ventricular neuroepithlium and Cajal-Retzius cells.

A.神经元死亡我们制备了针对巴克（一种促进神经元凋亡的蛋白质）的多克隆抗体，从而通过蛋白质印迹和免疫染色研究了其在人脑中的表达。1996年，我们研究了与发育和衰老相关的变化，并证明巴克在胎儿和老年脑中的高表达。1997年，我们比较了唐氏综合征患者和对照组患者的巴克免疫反应性。在唐氏综合症患者的大脑中，与年龄相关的巴克蛋白上调过早发生。B.神经元分化我们制备了兔抗tuberin N-和C-末端的抗体，tuberin是负责结节性硬化症的TSC 2基因的产物。1996年，我们证明了tuberin在正常大脑中的表达。在发育过程中，块茎素含量随着年龄的增长而增加。相比之下，硬化性脑组织显示结节素的丢失，这在错构瘤病变（皮质结节和室管膜下巨细胞瘤）和组织学正常的皮质中都是严重的。肾和心脏错构瘤中也失去了免疫反应性。在1997年，我们观察到一个正常水平的tuberin表达局灶性皮质发育不良，从而表明结节性硬化症和皮质dysplasia.C之间的病理生理差异。神经元migrationWe延长免疫组化研究的LIS 1基因产物（PAF乙酰水解酶的45 k亚基），该缺陷是负责米勒-迪克无脑综合征。1996年，我们研究了LIS 1在各种迁移障碍中的表达，并证明LIS 1的缺失是该综合征特有的。在1997年，我们免疫染色人胎脑，并观察到心室神经上皮细胞和Cajal-Retzius细胞的强烈标记。