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Non-Clinical Study Service using Genetically Engineered Mouse Models

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  • 2017/09/14
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Non-Clinical Study Service using Genetically Engineered Mouse Models

Trans Genic group offers the non-clinical study service using genetically engineered mouse models which were established in various research institutes through licensing agreement.

Lineup of Non-Clinical Study


Disease Genetically Engineered Mouse Models
Alzheimer’s disease APPosk-Tg mouse(Mouse prion promoter – Human APP E693Δ)
Neuropsychiatric disorders ProBDNF KI mouse(proBDNF R125M/R127L knock-in)
Dementia SJLB mouse (Mouse prion promoter – Human TAU N279K)
NASH NASH AIM KO mouse
Atopic dermatitis IL33 Tg mouse (K14 promoter – Mouse IL33)

※Prices vary depending on the study plan. Please contact us.
* Various studies including behavior, biochemical and genetic analyses are performed in Trans Genic group.

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Alzheimer’s disease research model

Alzheimer’s disease research model Alzheimer’s disease and the amyloid hypothesis
Alzheimer’s disease (“AD”) is a progressive neurodegenerative disease accompanied by the decline in cognitive function. The pathological change in brain includes the accumulation of insoluble aggregate consisting of amyloid β (“Aβ”), called senile plaque, the accumulation of insoluble aggregate
consisting of TAU protein, called neurofibrillary tangle (“NFT”), and brain atrophy.
One of the hypotheses which explain ADpathogenesis is “Amyloid hypothesis” as below:

  • 1.Aβ forms soluble aggregate (Aβ oligomer) and insoluble aggregate (Aβ fibril).
  • 2.Aβ aggregates induce hyperphophorylation and auto-aggregation of TAU protein, forming abnormal aggregated TAU, NFT.
  • 3.NFT induces neuronal cell death.
  • 4.Brain atrophy progresses and cognitive impairment

Oligomer hypothesis and Osaka mutation
In the early amyloid hypothesis, it was considered that neuronal cell death induced by Aβ fibril (insoluble aggregate in senile plaque) causes cognitive decline. However, since Aβ level necessary for neuronal cell death is too high compared with the physiological level in vivo, and also severity of AD patients does not correlate with the amount of Aβ fibril in the brain, the existence of toxic substance other than Aβ fibril was suggested. Consequently, “Oligomer hypothesis”, in which Aβ oligomer leading synaptic dysfunction in physiological concentration might be important for AD development, was advocated. However, because both Aβ oligomer and Aβ fibril exist in the brain of AD patients, it was difficult to determine which form of Aβ contributes to AD pathogenesis.
he research group of Dr. Takami Tomiyama and Dr. Hiroshi Mori (Osaka City University) identified the novel gene mutation from a familial AD case in 2008. The mutation (APPosk, E693Δ) discovered was one amino acid deletion in amyloid precursor protein (“APP”) gene. Aβ peptide derived from APPosk, which lacks glutamate at position 22 (Aβ E22Δ), shows unique property of enhanced oligomerization but no fibrillization. Senile plaque was not detected in the brain of AD with APPosk mutation. The discovery of this mutation proved for the first time that AD develops by Aβ oligomer alone.

APPosk-Tg mouse
Average±SE.*p<0.05,** p<0.01 t-test

APPosk-Tg mouse
APPosk-Tg mice express human APPosk mutant protein in the brain. APPosk-Tg mice develop the accumulation of Aβ oligomer accompanied by aging, however, there is no senile plaque observed even at 24 months of age. On the other hand, various AD symptoms including synaptic loss, hyperphosphorylation of TAU protein, activation of glial cells, and neuronal cell death are observed in this mouse line. From these results, APPosk-Tg mice are considered to be the mouse model supporting “oligomer hypothesis”, and also helpful for the research of AD pathogenesis by Aβ oligomer, therapeutic development, and drug discovery.

< References >
■ Tomiyama T., Nagata T., Shimada H., Teraoka R., Fukushima A., Kanemitsu H., Takuma H., Kuwano R., Imagawa M., Ataka S., Wada Y., Yoshioka E., Nishizaki T., Watanabe Y. and Mori H. A new amyloid β variant favoring oligomerization in Alzheimer's-type dementia. Ann. Neurol. 63, 377-387 (2008).
■ omiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., Nishitsuji, K., Ito, K., Shimada, H., Lambert, M.P., Klein, W.L. and Mori, H.
A mouse model of amyloid β oligomers: Their contribution to synaptic alteration, abnormal Tau phosphorylation, glial activation, and neuronal loss in vivo. J. Neurosci. 30, 4845-4856 (2010).
■ Umeda T., Ono K., Sakai A., Yamashita M., Mizuguchi M, Klein W.L., Yamada M., Mori H. and Tomiyama T. Rifampicin is a candidate preventive medicine against amyloid β and tau oligomers.Brain 139, 1568-1586 (2016).

< Patent >
■ WO/2006/038729 “Mutated Amyloid Protein”

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Neuropsychiatric disorder research model

BDNF and neuropsychiatric disorder BDNF and neuropsychiatric disorder
Brain derived neurotrophic factor (BDNF) is one of the neurotrophic factor, which has received the attention to be a substance relevant to various neuropsychiatric disorders such as depression in recent years. It is shown that BDNF is important for the formation, development, and maintenance of neural network, synaptic plasticity, as well as memory formation and learning. Mature BDNF is produced by the cleavage of proBDNF, precursor of BDNF. Mature BDNF binds to tyrosine kinase receptor (TrkB), and induces cell survival, cell differentiation and synaptogenesis. On the other hand, proBDNF binds to p75NTR receptor, and induces apoptosis and suppression of neurite elongation.

proBDNF KI mouse proBDNF KI mouse
Dr. Masami Kojima (the National Institute of Advanced Industrial Science and Technology) considered that impaired processing of proBDNF and deficient secretion might be involved in neuropsychiatric disorder including depression, and generated the knock-in mice in which mutation to suppress proBDNF processing is introduced. This knock-in mouse exhibits prolonged immobility time in the tail suspension test. ProBDNF knock-in mouse is valuable for the study of neuropsychiatric disorder including dementia, and contributes to the therapeutic development and drug discovery.

< References >
■ Mizui, T., Ishikawa, Y., Kumonogoh, H. and Kojima, M. Neurobiological actions by three distinct subtypes of brain-derived neurotrophic factor: Multi-ligand model of growth factor signaling.Phamacol. Res. 105, 93-98 (2016 review).
■ Mizui, T., Ishikawa, Y., Kumanogoh, H., Lume, M., Matsumoto, T., Hara, T., Yamawaki, S., Takahashi, M., Shiosaka, S., Itami, C., Uegaki, K., Saarma, M. and Kojima, M. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met.Pro. Nat. Aca. Sci. 112, E3067-3074 (2015).
Koshimizu, H., Hazama, S., Hara, T., Ogura, A. and Kojima, M. Distinct signaling pathways of precursor BDNF and mature BDNF in cultured cerebellar granule neurons.Neurosci. Letters 473, 229-232 (2010).
■ Koshimizu, H., Kiyosue, K., Hara, T., Hazama, S., Suzuki, S., Uegaki, K., Nagappan, G., Zaitsev, E., Hirokawa, T., Tatsu, T., Ogura, A., Lu, B. and Kojima, M. Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival.Mol. Brain 2, 27 (2009).

< Patent >
■ JP5414012B2 “Mutant BDNF gene-introduced knock-in mice”

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Dementia research model


Dementia and TAU
There are many kinds of dementia such as AD, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is known as an autosomal dominant disease. The signs and symptoms such as motion-impairment and cognitive dysfunction usually become noticeable in a person’s forties to sixties, and after a certain period, affected individuals may develop serious dementia. It is known that FTDP-17 is caused by the abnormality of TAU protein. Abnormal accumulation of TAU protein is considered to be directly associated with neural death, and the cause of AD. Some genetic mutations on TAU gene are already reported, including N279K mutation. This is the point mutation causing amino-acid replacement.

SJLB mouse SJLB mouse
SJLB mice express TAU protein with N279K mutation in the brain. SJLB mice exhibit the impairment of spatial ability and risk avoiding ability, therefore, are considered to be useful as the mice model of cognitive impairment to investigate the treatment method and therapeutic agents targeting TAU protein.
As a control mouse, UBJAP mouse which expresses human wild-type TAU is available.

< References >
■ Taniguchi, T., Doe, N., Matsuyama, S., Kitamura, Y., Mori, H., Saito, N. and Tanaka, C.Transgenic mice expressing mutant (N279K) human tau show mutation dependent cognitive deficits without neurofibllary tangle formation. FEBS letters 579, 5704-5712 (2005).

< Patent >
■ JP2011043428A "Inspection method of Parkinsonism using non-human animal model"

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NASH (nonalcoholic steatohepatitis) model


NASH
NASH (nonalcoholic steatohepatitis) is liver inflammation caused by a buildup of fat in the liver. It develops in patients with risk factors such as obesity, dyslipidemia, glucose intolerance, overeating, obesity (visceral fat type), and lack of exercise. Persistent inflammation causes fibrosis, scar tissue around the liver and nearby blood vessels. In the most severe stage, the damage becomes permanent and can lead to liver failure such as cirrhosis and liver cancer. Since NASH was first identified in 1980, it has been increasingly recognized. The estimated number of patients is 3,000,000 in Japan and 30,000,000 in US.。

AIM KO mouse
AIM (Apoptosis Inhibitor of Macrophage) is a protein produced by macrophages and secreted to blood. AIM is identified by Dr. Toru Miyazaki and colleague at University of Tokyo as a factor which involves in the survival of macrophage. The amount of AIM in blood varies depending on ages, sex and some disease situation. AIM is incorporated from extracellular space to inside of cells including adipocytes and hepatocytes by endocytosis and inhibits fatty acid synthetase to suppress the accumulation of intracellular neutral fat. This suggests the possibility that AIM in the blood suppresses the progression of obesity and fatty liver. Dr. Miyazaki’s group produced AIM KO mice (AIM-/-) in which the function of AIM was disrupted. AIM KO mice exhibit the phenotypes of fatty liver, fibrosis, inflammation, and non-regenerative hepatocyte hyperplasia with high fat diet. These phenotypes reflect the stages of the progression of human NASH, and AIM KO mice are considered to be a disease model of NASH. AIM KO mice are useful for development of the treatment method and therapeutic agents targeting NASH and subsequent diseases.
非アルコール性脂肪肝炎 (NASH) モデル

< References >
■ Kurokawa, J., Arai, S., Nakashima, K., Nagano, H., Nishijima, A., Miyata, K., Ose, R., Mori, M., Kubota, N., Kadowaki, T., Oike, Y., Koga, H., Febbraio, M., Iwanaga, T. and Miyazaki, T.
Macrophage-derived AIM is endocytosed into adipocytes and decreases lipid droplets via inhibition of fatty acid synthase activity. Cell Metabol. 11, 479-492 (2010).

■ Maehara, N., Ara, S., Mori, M., Iwamura, Y., Kurokawa, J., Kai, T. Kusunoki, S., Taniguchi, K., Ikeda, K., Ohara, O.,Yamamura, K. and Miyazaki, T.
Circulating AIM prevents hepatocellular carcinoma through complement activation. Cell Rep. 1, 61-74 (2014).

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Atopic dermatitis model


Atopic dermatitis and IL33
Atopic dermatitis is a type of inflammation of the skin which main symptom is itchy repeating dermatitis.
The number of patients reaches 10 – 20% of population. The cause is still unknown, although many hypotheses have been presented.
IL33 is an interleukin which localizes in the nuclear of various epithelial cells and endothelial cells, and secreted to extracellular space to activate immune cells including lymphocyte, adipocyte, basophils and eosinophils. IL33 is considered to be involved in allergic diseases such as hay fever, nasal inflammation and asthma, arthritis, diabetes and inflammatory bowel disease. IL33 is also expressed in the skin of atopic dermatitis patients.

IL33 Tg mouse
Dr. Yasutomo Imai and Dr. Kiyofumi Yamanichi produced transgenic mice in which IL33 gene is expressed in the skin under the regulation of skin specific keratin 14 promoter to investigate a role of IL33 in skin.
As a result, it was shown that the 100% of transgenic mice spontaneously developed atopic dermatitis after 8 weeks old. The transgenic mice shows itchy dermatitis on body surface especially on face, ears and tails.
They also show the infiltration of inflammatory cells into dermis, increased number of adipocytes, increased amount of chemokines, and higher levels of blood IgG and histamine. These observations suggest the mechanism that the increase amount of IL33 in skin activates adipocytes and type II innate lymphoids, resulting increased number of eosinophils causes atopic dermatitis.
Atopic dermatitis model
Thus, IL33 Tg mice are considered to be a good model which reproduce the status of atopic dermatitis and expected to be useful for development of the treatment method and therapeutic agents targeting this disease.
Atopic dermatitis model

< References >
■ Imai, Y., Yasuda, K., Sakaguchi, Y., Haneda, T., Mizutani, H., Yoshimoto, T., Nakanishi, K., Yamanishi, K.
Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc. Natl. Acad. Sci. U.S.A. 110, 13921-13026 (2013).

< Patent >
■ PCT/JP2014/061931 "ATOPIC DERMATITIS MODEL ANIMAL AND USE THEREOF"

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