1993 Fiscal Year Final Research Report Summary
Molecular biology for Alzheimer's disease
| Project/Area Number |
03557037
|
|---|
| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
Principal Investigator |
YUASA Tatsuhiko Tokyo Medical and Dental University, Dept of Neurology, Ass.Prof., 医学部・神経内科学講座, 助教授 (10115090)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KATSUKI Motoya Medical Institute of Bioregulation, Kyushu University, Prof., 生体防御医学研究所・細胞化学部門, 教授 (20051732)
UCHIDA Yoko Tokyo Metropolitan Institute of Gerontology, Dept of Neuropathology, Researcher, 神経病理, 研究員 (60133633)
IHARA Yasuo Institute of Brain Research, University of Tokyo, Dept of Neuropathology, Prof., 医学部・脳研究所・神経病理学, 教授 (60114386)
TSUJI Shoji Brain Research Institute, Niigata University, Dept of Neurology, Prof., 脳研究所・神経内科学, 教授 (70150612)
|
|---|
| Project Period (FY) |
1991 – 1993
|
| Keywords | Alzheimer's diseaase / Growth inhibitory factor (GIF) / Metallothionein / Gene targeting / Metal responsive-element / cDNA |
|---|
| Research Abstract |
Growth inhibitory factor (GIF) is down-regulated in Alzheimer's disease (AD) brains. We have cloned a full-length cDNA for human GIF gene and found a striking homology to metallothioneins (MTs). In contrast to MT gene, the GIF gene expression is found exclusively in the nervous system. Northern blot analysis revealed that the GIF mRNA expression is drastically decreased in AD brains. To analyze the mechanism of this down-regulation, we isolated the human and mouse GIF genes. These genes consist of three exons, are approximately 1 kb long. A comparison of the human and mouse GIF genes showed several conserved sequences, including the putative AP-2, SP-1, TATA-binding protein and metal-responsive elemnts (MRE). A sequence similar to human gfa common sequence (hgcs), recently identified as the sequence for an astrocyte-specific transcriptional factor, is present in the promoter of these GIF genes.
Because GIFs are considered new members of the metallothionein family which are associated with resistance to the toxic effect of metals, we examined the effects of modulation of GIF transcriptional levels using heavy metals and cytokines in primary culture of mouse astrocyte cells. Stimulation by Cu^<2+> and Zn^<2+> induced GIF, whereas stimulation by IL-1 and EGF inhibited the transcription of GIF.These results indicate that several growth factors or cytokines regulate GIF synthesis and play a important part in regulation of the direction and extent of nerve growth. To disrupt GIF sesquences in mouse embryonic stem cells, we made a replacement vector containing a 6-kb genomic fragment that included the entire the GIF gene. The part of first exon was deleted and a neo cassette was inserted in the deleted position. Now we are trying to produce the GIF deficient mouse to elucidate the function of the GIF gene in vivo.
|
