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Non-human animal model of oligodendrocyte developmental disorder 実績あり

外国特許コード F110005035
整理番号 A031-35WO
掲載日 2011年8月18日
出願国 アメリカ合衆国
出願番号 71211803
公報番号 20050210538
公報番号 7332644
出願日 平成14年5月2日(2002.5.2)
公報発行日 平成17年9月22日(2005.9.22)
公報発行日 平成20年2月19日(2008.2.19)
国際出願番号 JP2002004405
国際公開番号 WO2002091820
国際出願日 平成14年5月2日(2002.5.2)
国際公開日 平成14年11月21日(2002.11.21)
優先権データ
  • 特願2001-146338 (2001.5.16) JP
  • 2002JP004405 (2002.5.2) WO
発明の名称 (英語) Non-human animal model of oligodendrocyte developmental disorder 実績あり
発明の概要(英語) The objects of the present invention is to provide a preventive method for the progress of neuropsychiatric disorders, a therapeutic agent for neuropsychiatric disorders, a screening method thereof, and a therapeutic method through the analysis of the mechanisms leading to neuropsychiatric disorders such as Nasu-Hakola diseases and the like.
The non-human animal model of oligodendrocytes developmental disorders was generated by making the DAP12 gene function deficient on its chromosome.
The DAP12 knockout mouse develops myelination disorders including hypomyelinosis in the brain, particularly in the frontal head and the thalamus, further leading to neuropsychiatric disorders such as Nasu-Hakola disease and the like with aging.
The screening method for a therapeutic agent, the diagnostic method, and the therapeutic method, wherein the DAP12 knockout mouse developing these disorders are used, have been developed.
従来技術、競合技術の概要(英語) BACKGROUND OF THE INVENTION
DAP12 (DNAX Activation Protein 12) is indicated to be a transmembrane protein containing an activation motif, ITAM, which binds to ZAP-70 or Syk through phosphorylation.
It is known that DAP12 is encoded by a single-copy gene located on the 19q13.1 in humans and also exists in mice.
It is also known that mRNAs of the DAP12 are largely expressed in monocytes, dendritic cells, and natural killer cells, and that DAP12 is not only involved in activated signaling of a KAR group, but also associates with a human signal regulatory protein (SIRP) beta 1, a human or a murine myeloid DAP12-associating lectin (MDL)-1, and a triggering receptor expressed on myeloid cells (TREM).
It is reported that DAP12 also associates with KAR molecules, which belong to the C-type lectin family, such as CD94/NKG2C and the like, and performs its function (Immunity 8, 693-701, 1998; J. Immunol. 161, 7-10, 1998; J. Immunol. 160, 4148-52, 1998).
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease (Suppl. 232, 1-173, 1972; Acta Pathol.
Jpn. 23, 539-558, 1973; J. Med. Genet. 34, 753-757, 1977) is a central nervous system disorder found in Japan and Finland.
In addition to the formation of bone cysts, patients of Nasu-Hakola disease develop psychotic symptoms, such as personality changes, inevitably progressing to pre-senile dementia.
The mutation found in Finnish patients is a 5.3 kb deletion in the DAP12 [KARAP (Killer activating receptor associated protein)/TYROBP (protein tyrosine kinase binding protein)] locus, while another defect in Japanese patients is a single-nucleotide deletion in the third exon of the gene.
Both are known to be caused by the loss of function of DAP12, a membrane adaptor protein (J.
Immunol. 158, 5083-5086, 1997; Nature 391, 703-707, 1998) found initially in the immune system (Nature Genet. 25, 357-361, 2000).
However, it has not yet known whether psychotic symptoms are caused by the deficiency of DAP12.
On the other hand, in an animal model of dementia, only methods for inducing cerebral ischemia or accumulating amyloid protein have been developed, and the utility values of such model animals as a base for analyzing the mechanisms progressing to dementia and for preventing the progression of dementia have not been efficient.
It has been known in recent years that the deficiency of DAP12 induces the onset of neuropsychiatric disorders progressing to juvenile dementia called Nasu-Hakola disease (Nature Genet. 25, 357-361, 2000).
However, the fundamental cause has not been verified, and it is not known whether the frontal lobe- and thalamus-specific dysmyelination occurs in DAP12 deficient mice that show symptoms of schizophrenia.
The aforementioned Nasu-Hakola disease is a recessive hereditary disease, which is fatal and inevitably progressing to presenile dementia following the formation of bone cysts and neuropsychiatric disorders.
The object of the present invention is to provide the following: a non-human animal model of oligodendrocyte developmental disorder whose DAP12 (DNAX Activation Protein 12) gene function is deficient on its chromosome; a screening method for a developmental promoter or a developmental suppressor of oligodendrocytes, or, a promoter or a suppressor of myelinogenesis, wherein the non-human animal model of oligodendrocyte developmental disorder is used; a screening method for a therapeutic agent for neuropsychiatric disorders; a diagnostic method for neuropsychiatric disorders, which enable to develop a preventive method for the progress of neuropsychiatric disorders and a therapeutic method for neuropsychiatric disorders by analyzing the mechanisms progressing to neuropsychiatric disorders such as Nasu-Hakola disease, dementia, schizophrenia, schizotypal personality disorders, obsessive-compulsive disorders, Huntington's disease and Tourette's syndrome, etc.
The present inventors have analyzed the physiological function of DAP12, generated a mouse whose DAP12 gene function is deficient on its chromosome, namely a DAP12 knockout mouse, and examined the brain.
The present inventors have found that demyelination, namely myelination disorder including hypomyelinosis, can be seen particularly in the frontal head and thalamus, and that this disorder is attributed to the inhibition of differentiation, development, intracerebral transfer in the cell due to the deficiency of DAP12 in oligodendrocytes that plays a role of myelinogenesis.
The present inventors have further found that deficiency can be seen in the reflective power, despite that muscle and the like are normal by the behavioral analysis of the above-mentioned DAP12 knockout mouse, and clarified that psychotic symptoms similar to schizophrenia can be seen with aging.

特許請求の範囲(英語) [claim1]
1. A transgenic mouse model showing Nasu-Hakola disease, wherein the transgenic mouse comprises a homozygous disruption in its endogenous DAP12 (DNAX Activation Protein 12) gene and shows hypomyelinosis of the thalamus, and wherein the homozygous disruption includes the promoter region and exons 1, 2, and 3.
[claim2]
2. The transgenic mouse model of claim 1, wherein the homozygous disruption in the DAP12 gene can be pheonotypically exhibited as a myelinogenesis developmental disorder.
[claim3]
3. The transgenic mouse model of claim 1 or 2, further showing a disease selected from the group consisting of dementia caused by Nasu-Hakola disease, schizophrenia caused by Nasu-Hakola disease, schizotypal personality disorders caused by Nasu-Hakola disease, obsessive-compulsive disorders caused by Nasu-Hakola disease, or Tourette's syndrome caused by Nasu-Hakola disease.
[claim4]
4. The transgenic mouse model of claim 1 or 2, further showing dementia caused by Nasu-Hakola disease.
[claim5]
5. The transgenic mouse model of claim 1, weherein the expression of myelin basic protein in the brain is weak in regions where DAP 12 is strongly expressed in wild-type mice.
[claim6]
6. The transgenic mouse model of claim 1, wherein the transgenic mouse exhibits an impairment in sensorimotor gating as compared to wild-type mice.
  • 発明者/出願人(英語)
  • TAKAI TOSHIYUKI
  • ASO HIROAKI
  • FUJIWARA MICHIHIRO
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
国際特許分類(IPC)
米国特許分類/主・副
  • 800/9
  • 536/23.1
  • 800/18
参考情報 (研究プロジェクト等) CREST Host Defense Mechanism AREA
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