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Hosokawa Masanori

    Department of Nursing　Dean/Professor
    Graduate Schools of Nursing　Professor
Last Updated :2024/02/01

Researcher Information

Degree

  • Doctor of Medicine（Kyoto University）

J-Global ID

Research Interests

  • 細胞生物学   基礎老化学   実験病理学   Cell Biology   Gerontology   Experimental Pathology   

Academic & Professional Experience

  • 2019/04 - Today  Kyoto Koka Women's UniversityThe Faculty of Health Science学部長
  • 2017/04 - Today  愛知県医療療育総合センター発達障害研究所名誉所長
  • 2017/04 - Today  Kyoto Koka Women's UniversityThe Faculty of Health Science, The Department of Nursing教授
  • 2008 - 2017/03  Institute for Developmental Research, Aichi Human Service Center所長・病理学部長
  • 2002 - 2017/03  Institute for Developmental Research, Aichi Human Service Center副所長・病理学部長
  • 1998 - 2002  Kyoto UniversityInstitute for Frontier Medical Sciences助教授
  • 1989 - 1998  京都大学胸部疾患研究所老化生物学分野助教授
  • 1979 - 1989  京都大学胸部疾患研究所(結核胸部疾患研究所)病理学部門助手

Education

  •        - 1976  Kyoto University  Faculty of Medicine

Association Memberships

  • 老化促進モデルマウス（SAM)学会   日本基礎老化学会   日本病理学会   JAPANESE SOCIETY ON SEVERE MOTOR AND INTELLECTUAL DISABILITIES   THE JAPANESE TERATOLOGY SOCIETY   

Published Papers

Works

  • 長寿医療研究委託事業(厚生労働者)
    2000
  • Research Grant for Longevity Sciences
    2000

MISC

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2017/03 
    Author : Hosokawa Masanori
     
    Neonatal hypoxic-ischemia is a condition that result in severe neurologic deficits in children. Periventricular leukomalacia (PVL), a brain hypoxic-ischemia affecting premature infants is commonly associated with cerebral palsy. A brain of premature infants is particularly susceptible to cerebral white matter injury that disrupts the normal progression of developmental myelination. In this study, we investigated pathogenesis of PVL using induced culture cells and animal models. While we are performing experiments, we found that (1) monoacylglycerol lipase (MAGL), an important factor in neuroinflammation, regulates phagocytosis, but not LPS-mediated cytokine induction in microglia. (2) Cholesterol trafficking in immature oligodendrocytes play an important role in maturation of the cells and myelination. These findings will provide a possible preventive approach for white matter injury in PVL.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012/04 -2015/03 
    Author : KOUCHI Zen; HOSOKAWA Masanori; SHIMADA Atsuyoshi; ENOKIDO Yasushi; CHIBA Yoichi
     
    It has been known that monoacylglycerol lipase (MAGL) is involved in wiring process of neural network in brain development, however, its pathological function in inflammatory condition remains unknown. We found that MAGL transcription was downregulated in neonatal brain subjected to hypoxic/ischemic stress and primary microglia treated with lipopolysaccharide (LPS). Microglial MAGL was transcriptionally regulated by Stat6 and its protein was rapidly degraded by proteasome in steady state. LPS treatment inhibited its degradation, resulting in its stabilization in microglia. Intrinsic MAGL was not prerequisite for LPS-dependent induction of several inflammatory cytokines such as IL6 in normoxic or hypoxic conditions, whereas it promoted phagocytosis mediated by Fcγ receptor in microglia.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2006 -2008 
    Author : SHIMADA Atsuyoshi
     
    神経変性疾患では特定の脳領域に変性が進行する傾向があるが、そのメカニズムは不明である。ここでは、ニューロン変性が加齢に伴って大脳辺縁系に選択的に進行するSAMP10マウスを神経変性のモデルとして解析した結果、神経変性の原因として、タンパク質分解系であるプロテアソーム活性の低下、軸索を構築する主要な細胞骨格タンパク質であるα-internexinのリン酸化の亢進が重要であることがわかった。神経変性の原因遺伝子については、15番染色体の特定の領域に存在することは突き止めたものの、同定にはさらなる研究が必要である。
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2005 -2006 
    Author : 細川 昌則; 千葉 陽一; 島田 厚良; 佐藤 衛; 齊藤 優子
     
    老化促進モデルマウスSAMP系統は、対象のSAMR1系統マウスと比較して、ミトコンドリア機能障害により高酸化的ストレス状態を示す。この高酸化ストレス状態は培養線維芽細胞の培養加齢を促進し、抗酸化剤の添加は、培養加齢の促進を部分的に軽減する。SAMR1マウスとSAMP11系統マウス母親を相互に入れ替えた交雑で作製したF1マウスの培養加齢は、SAMR1マウスと変わらず、培養加齢の促進は劣性形質であることが示された。またF1交雑マウスの培養加齢に母親系統の影響は見られず、SAMP系統マウスのミトコンドリア機能障害には核遺伝子に由来する電子伝達系サブユニットが関係し、また機能障害が劣性の形質であることが推測された。 SAM系統マウスの成立メカニズムは、交雑により形成された遺伝子プールから、老化促進、寿命、老化形質などに基づき、選抜交配を繰り返すことによると考えられている。マウスゲノムデーターベースの情報を基に、SAMP11系統の近縁系統であるSAMP10系統とSAMR1系統のマイクロサテライトマーカーに多型が認められる第1番〜第19番染色体領域に存在する、ミトコンドリア電子伝達系サブユニットをコードする遺伝子を検索した。複合体Iに関係する37遺伝子のうち7遺伝子、複合体IIIに関係する8遺伝子の内2遺伝子、複合体IVに関係する16遺伝子の内1遺伝子、複合体Vに関係する16遺伝子のうち5遺伝子が有力な検討対象となることが判った。これまでの研究で、SAMP系統マウスのミトコンドリア電子伝達系複合体I、III、Vの機能不全が示されており、今回の結果により、関連サブユニットの探索を一歩進めることができた。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2003 -2004 
    Author : SHIMADA Atsuyoshi; HOSOKAWA Masanori
     
    A perturbation in ubiquitin-proteasome pathway plays a critical role in the accumulation of abnormal proteins in various neurodegenerative disorders. We studied neuronal cytoplasmic ubiquitinated inclusions that primarily affected the limbic system of SAMP10 (P10), a mouse model of cerebral degeneration, and age-related changes in brain proteasome activity in P10 using SAMR1 (R1) as a control. Based on ubiquitin-immunostained brains sections, the rate of inclusion-bearing neurons increased with aging relatively rapidly in P10. Ubiquitinated inclusions were densely distributed in the diagonal band, septum, accumbens, amygdala, hypothalamus, medial thalarnus, ventral hippocampus, subiculum and piriform, entorhinal, insular and cingulate cortices. Fluorogenic peptide substrate assays of tissue homogenates prepared from the limbic system revealed that proteasome activity of P10 at 3,7,12 and 17 months was respectively 181,105,82 and 48 (pmol AMC/min/mg protein) and that of R1 was respectively 150,134,126 and 88. Therefore, aging P10 mice develop neuronal inclusions in the limbic system because ubiquitinated abnormal proteins accumulate due to a decrease in proteasome activity.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2002 -2004 
    Author : HIGUCHI Keiichi; MORI Masayuki; SAWASHITA Jinko; HOSOKAWA Masanori; NAKAMURA Akihiro
     
    1)Genetic Analysis of Accelerated Senescence and Age-related Disorders in SAM mice : 1)We observed that the congenic mouse strains of the two chromosomal regions (Chr. 5 and 7) responsible for the accelerated senescence in SAMP1 mice, have shorter life span than the control strain mice. 2)We have made congenic, sub-congenic and finaly sub-subcongenic mouse strains between osteoporotic SAMP6 and normal SAMP2 mice of three chromosomal regions (Pbd-1, 2, 3) responsible for osteoporosis (low peak born mass) in SAMP6 mice. We compared the expression levels of genes in the "critical region of Pbd-2" among congenic mouse strains and found that Sfr4 (decoy receptor for Wint protein) is expressed more than 10 times higher in the bone of SAMP6 mice compared with SAMP2. We now propose the hypothesis that the increased expression of Sfr4 inhibit the signal transduction of Wint and lead to lower differentiation of osteoblast in SAMP6 mice. 3) We performed genetic analysis using amyloidosis prone SAMP1 mice and less amyloidogenic A/J mice, both of which have amyloidogenic Apoa2^c allele to determine the modifier genes of amyloidosis. We identified two chromosomal regions (Chr. 14, and 19) responsible for inhibition of amyloidosis. 2)Mouse Testis Transcriptome Revealed Using Serial Analysis of Gene Expression (SAGE) : We assayed gene expression profiles (transcriptome) of young and old SAMR1 and SAMP1 mice using SAGE method. We determined over 19,000 genes and found that the reduction of oligozoospermia specific transcription factors lead to the reduction of many genes down stream of them. 3)Collaborative Works Using SAM Strains : Diurnal rhythm disorder of behavioral activity in SAMP1 mice was partially normalized by spontaneous wheel running. We performed genetic analysis using SAMP10 mouse strain and control SAMRI strain to identify the genes responsible for age-related learning disability and brain atrophy in SAMP10 strain. We are collaboration with Kaneka Co and Kohchi University School of Medicine to analyze anti-aging effects of Coenzyme Q10 and beta-carotene rich Algae.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2002 -2003 
    Author : HOSOKAWA Masanori
     
    The SAM strains are consisting of a series of SAMP and SAMR strains. When compared with the SAMR strains, the SAMP strains of mice show a more accelerated senescence process, shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes. The higher oxidative status and mitochondrial dysfunction were observed in various organs in SAMP strains of mice. The senescence acceleration is also observed during senescence in cultures of isolated dermal fibroblast-like cells from SAMP11 mice, and was associated with a higher oxidative status. The quantity of reactive oxygen species (ROS) was greater than that in the SAMR1 cells, a control cells, after the 7th day in culture. Enzymatic activity and mRNA quantity of the antioxidant enzymes could not account for the difference in ROS production. Mitochondria with degenerated ultrastructures and low membrane potential were increased in the SAMP11 cells with time. We observed these dysfunctional mitochondria having an abnormal appearance in various tissues from old SAMP mice. The SAMP10 mice developed diffuse atrophy in the cerebral neocortex, especially frontal cortex, with advancing age. The Number of neurons in the cortex decreased with aging. TUNEL assays revealed an age-related increase in the number of TUNEL-positive cells with aging and these cells were interpreted to undergo DNA damage through a mechanism other than apoptosis. There were also intra neuronal inclusions in aged SAMP10 mice. We have developed a culture system of neuronal cells and astroglia from these SAMP and SAMR strains including SAMP10 mice. Purity of the cells in each culture was over 99%. Now we are investigating the molecular basis of the neuronal degeneration under intrinsic hyperoxidative status in SAMP10 mice.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2002 -2003 
    Author : TSUBOYAMA Tadao; HOSOKAWA Masanori; SHIMIZU Motoyuki
     
    The correlation was investigated between bone mineral density (BMD) of lumber spine or proximal femur and polymorphic genotype of several genes in 73 healthy young women. Among the genes studied, three had already been reported as candidate genes controlling bone density, i. e., Estrogen receptor α, Vitamin D receptor, and 5, 10-Methylenetetrahydrofolate Reductase (MTHFR). Another gene, IFP35, was a new candidate gene, from the study of an animal model using interval-specific congenic mice between SAMP6 and SAMP2 strains. There was no correlation between BMD and polymorphism of Estrogen receptor α and Vitamin D receptor, while VV genotype of MTHFR showed significantly higher BMDs in 1^, 2^, and 3^ lumber spine than other genotypes. Regarding IPF35, direct sequencing of all the exons revealed no polymorphism among the population studied. Sub-congenic strains between SAMP6 and SAMP2 confirmed the existence of loci regulating bone density in a 3 cM interval on Chr 13. All the exons of 74 genes in this interval were sequenced, and polymorphisms with amino acid substitution were found in 15 genes. Among them, Ggps1 (gerany1-gerany1 diphosphate synthase 1) and Tbce (tubullin specific chaperone E) seemed to be possible candidate genes.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1999 -2000 
    Author : TSUBOYAMA Tadao; HOSOKAWA Masanori
     
    Previously, we identified two quantitative trait loci (QTLs) specifying the peak relative bone mass on chromosomes (Chrs) 11 and 13 by interval mapping in two mouse strains, SAMP2 and SAMP6. The latter strain is an established murine model of senile osteoporosis and exhibits a significantly lower peak relative bone mass than SAMP2. In this study, we constructed interval-specific congenic strains in order to dissect the polygenic trait into single gene factors. By seven consecutive backcrosses and intercrossmating of the N7mice, four congenic strains (P2.P6-pbd1^a, P2.P6-pbd2^a, P6.P2-pbd1^b, P6.P2-pbd2^b) were produced. P2.P6-pbd1^a and P2.P6-pbd2^a had a SAMP6-derived 48cM interval from Chr 11 and a SAMP6-derived 15cM interval from Chr 13, respectively, on a SAMP2-derived background. To the contrary, P6.P2-pbd1^b and P6.P2-pbd2^b had a SAMP2-derived 32cM interval from Chr 11 and SAMP2-derived 15cM interval from Chr 13, respectively, on a SAMP6-derived background. Microdensitometry, dual-energy X-ray absorptiometry, and peripheral quantitative computed tomography revealed lower bone density in P2.P6-pbd1^a and P2.P6-pbd2^a than in the background SAMP2 mice. These measurements showed lower bone density in P6.P2-pbd1^b and P6.P2-pbd2^b than in the background SAMP6 mice. These results confirmed the existence of loci regulating bone density on Chr 11 and Chr 13 in the SAM stains.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1997 -1998 
    Author : HOSOKAWA Masanori; HIGUCHI Keiichi
     
    The chromosomes of accelerated senescence-prone, short lived, 9 strains of SAMP and accelerated senescence-resistant, long lived, 3 strains of SAMR were typed with microsatellite markers. Comparison of the distribution of loci in the SAMP and SAMR strains revealed notable differences in the Chrs 4, 14, 16 and 17. This indicted that some of these chromosomal sites might contain the genes responsible for senescence acceleration. The whole genome scan for quantitative trait Ioci (QTLs) specifying peak bone mass was performed with the F2 intercrosses of SAMP6, senile osteoporosis model and SAMP2 with high peak bone mass. QTLs were identified on Chrs 11, 13 and X. Accelerated changes of in vitro aging were examined in fibroblast-like cells isolated from the dorsal dermis of newborn SAMP11 (accelerated senescence-prone, short lived) mice and were compared to the cell lines from SAMR1 (accelerated senescence-resistant, long lived) mice. The changes occurred more rapidly and at earlier population doublings in the cell lines from the SAMP11 mice. Aminoguanidine supplementation in this culture reduced the lipid peroxidation and delayed the senescence/crisis. The redox state and oxidative phosphorylation of the brain mitochondria from 2-month-old SAMP8 mice, an age-associated neurodegenerative model were investigated. The SAMP8 brain mitochondria demonstrated higher redox state and a higher activity of mitochondrial respiration with lower respiration control ratio. This indicated that an inefficient hyperactive state can exist in the mitochondrial electron transport system before the age-associated mitochondrial dysfunction develops.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1997 -1998 
    Author : HIGUCHI Keiichi; HOSOKAWA Masanori
     
    Amyloidosis refers to a group of diseases characterized by tissue deposition of amyloid fibrils. A single intravenous injection of a very small amount of the native mouse senile amyloid fibrils (AApoAII) induced severe systemic amyloid deposition in young mice having the amyloidogenic apoA-II gene (Apoa2^c). After AApoAII injection, amyloid deposition occurred rapidly, and advanced in an accelerated manner observed in spontaneous senile amyloidosis in mice. However, the injection of denatured AApoAII, native apoA-II in high density lipoprotein (HDL) and denatured apoA-II monomer which have the same primary structure but without a fibril conformation did not induce amyloidosis. These findings suggested that the nucleation-dependent polymerization found in vitro also occurs in vivo, and that the fibril conformation is required for the injected amyloid fibrils to act as seeds in viva. We injected AApoAII amyloid fibrils isolated from the liver of an old R1.P1-Apoa2^c mouse into the stomach of young mice using feeding needles for five consecutive days. After 2 months, all mice had AApoAII deposits in the lamina propria of the small intestine. Amyloid deposition extended to the tongue, stomach, heart and liver at 3 and 4 months after feeding. AApoAII suspended in drinking water also induced amyloidosis. Amyloid deposition was induced in young mice reared in the same cage for three months with old mice that had severe amyloidosis. Detection of AApoAII in feces of old mice suggested the transmission by eating of feces. Fibril conformation-dependent fibrillization is proposed as a general model of the pathogenesis of various kinds of amyloidosis occurring in viva. Further, we substantiated the transmissibility of AApoAII amyloidosis and presented the unique pathogenesis of amyloidosis "oral transmission of amyloid fibril conformation", that is, invasion of exogenous amyloid fibrils acts as seeds and changes the conformation of endogenous amyloid protein to polymerize into amyloid fibrils.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1997 -1998 
    Author : TSUBOYAMA Tadao; SHIGENO Chohei; HOSOKAWA Masanori
     
    The whole genome scan for quantitative trait loci (QTLs) specifying peak bone mass was performed with the F2 intercrosses of SAMP6, an established murine model of senile osteoporosis exhibiting a significantly lower peak bone mass, and SAMP2, exhibitinga higher peak bone mass. The bone masses of mice femurs were assayed photometrically using microdensitometry in 488 F2 progeny at 4 months of age, when the animals were reaching peak bone mass. Genetic markers were typed at 90 loci spanning all chromosomes except the Y.By interval mapping of 246 male F2 mice, two loci were identified with significant linkage to peak bone mass, one on chromosome 11 with a maximum lod score of 10.8 (22.2% of the total variance), and another on chromosome 13 with a maximum lod score of 5.8 (10.0%). Another locus on the X chromosome was suggestive of a QTL, We found no differences between SAMP6 and SAMP2 by sequencing genomic regions of G-CSF and a part of cDNA of chondroadherinin, which are candidate genes influencing low peak bone mass. We are constructing interval-specific congenic mice carrying appropriate SAMP6 and SAMP2 regions in order to refine the genetic locations of these QTLs. By cross-mating each congenic strain with parental strains and finding out the progenies that have a recombination within the putative QTL region detected in this study, it will be possible to make a high-resolution map and contract the QTL region. At present, we have established each N7 generation and homozygous mice by intercross-mating the N7 miceon Chr. 11, 13 and the X.These findings should be useful to elucidate the genetics of osteoporosis.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1995 -1996 
    Author : HIGUCHI Keiichi; HOSOKAWA Masanori
     
    Since, the effective treatment to amyloidosis is only the transplantation of the liver, we have done the basic studies for developing the gene therapeutic approach to amyloidosis. We used newly made congenic mice, R1.P1-Apoa2^c which are model mice of severe senile amyloidosis. 1.Genetic analysis of mouse senile amyloidosis : In the congenic mice, R1.P1-Apoa2^ which are heterozygous for wild type B and amyloidogenic type C apoA-II,amyloid deposition was significantly slight. This finding suggested the possible availability of gene therapeutic approach. 2.Primary culture of the hepatic cell of the amyloidogenic mouse strain : Hepatic cells were isolated and cultured from R1.P1-Apoa2^c mice. 3.Evaluation system for the effectiveness of the gene therapy : Since the onset of amyloid deposition is usually after 8-12 month of age, we tried to develop a new system for evaluation the effect of gene therapy in relatively short period. Intravenous injection of amyloid fibrils AApoAII in R1.P1-Apoa2^c induced amyloid deposition at one month after injection. In R1.P1-Apoa2^, amyloid deposition was significantly inhibited. 4.Adeno-virus with wild type apoA-II cDNA : Cosmid cassette (pAdexCAwt) which has human type 5 adenovirus (Ad5) and strong promoter unit, CAG (cytomegarovirus enhancer, chicken-actin promoter rabbit-globin polyA) was kindly provided by Dr.I.Saito in Tokyo University. Wild type apoA-II cDNA (Apoa2^c) was subcloned into Swal site of the cosmid and co-transformed with parental adeno virus DNA-TCP into the 293 cell. Several adeno viruses with wild type apoA-II cDNA produced by homologous recombination was selected.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 1995 -1995 
    Author : 坪山 直生; 細川 昌則
     
    退行期骨粗鬆症モデルマウスSAMP6は生後4カ月で低い最大骨量をとったのち、月齢とともにゆっくりと一定の速度で減少していく。また、対照のSAMP2はより高い最大骨量を示す。最大骨量が形成されるまでの2ヵ月齢の雄マウス(n=4)にh-PTH(1-34)60オg/kgを皮下注射し、所定の時間ののちに腎臓、大腿骨および脛骨を採取し生理食塩水で骨と骨髄を分離した。Northern blotでc-fos mRNAの発現量を調べ、免疫染色によりc-Fos蛋白の局在についても検討を行った。 骨ではPTH投与によりc-fos mRNAの発現量は30分でピーク値をとり、その後SAMP2では速やかに減少するが、SAMP6ではゆっくり減少し遷延化する傾向にあり、1時間でSAMP2にくらべ有意に発現が高かった。骨髄では統計学上、有意な変化は認められず、SAMP6、SAMP2間にも有意な差は認められなかった。PTH受容体が存在する腎臓でのc-fosの発現についても検討したが、腎臓での発現は骨よりも低く、SAMP6の方が低い傾向にあった。したがって、骨でみられた現象は組織特異的と考えられる。c-Fosの免疫染色の結果、PTH投与3時間後のSAMP6の大腿骨で骨芽細胞、破骨細胞様細胞、一部の骨細胞にc-Fos蛋白を認めた。 対照としたSAMP2に比べ、低い最大骨量をもつSAMP6では、PTHによって骨に誘導されるc-fos mRNAの発現量の多い状態がピーク後にみられ、その発現の減少が遅延していた。骨のリモデリング、特に骨吸収においてc-fosが重要な役割を果たしているので、PTHによって誘発されたc-fosが間接的に破骨細胞系に長く作用し、破骨細胞の成熟化、活性化を促進し、骨吸収の亢進状態をひきおこすのではないかと考えられる。この骨吸収の亢進が最大骨量低下の一因となっている可能性がある。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1991 -1993 
    Author : TAKEDA Toshio; HIGUCHI Keiichi; AKIGUCHI Ichiro
     
    deta / A4 arotein-like immunoreactivity was observed in the form of granular structures in various regions, including the medial septum, cerebral cortex, hippocampus, and so on. These increased in number with aging, predominantly in SAM-P/8 with deficits in lemory defici The severity of deficits in learning and memory closely correlated with the total area and number of vacuoles in magnocellular reticular formation (MGRF) of brain stem. MGRF lesioned SAM-R/1 mice showed a severe deterioration in passive avoidance tasks and an impairment in the acquisition stage of active avoidance performance. An inbred SAM-P/10 strain has been established as a model of agerelated brain atrophy. Morphometric studies showed that frontal cortex including prefrontal cortex, other neocortical regions, posterior piriorm cortex, anterior olfactory nucleus, amygdala, and caudate putamen were atrophy-prone regions. Shrinkage of the neuronal somata and loss of large neurons with age are unique for SAM-P/10, both of which bring about age-related atrophy Age-related changes in learning and memory skills of SAM-P/10 mice were investigated using a newly developed conditional avoidance retained the left-right turning discrimination in the T-maze and lost the ability to predict the forthcoming aversive shock by associating conditioned and unconditioned stimulus.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1991 -1992 
    Author : HIGUCHI Keiichi; HOSOKAWA Masanori; TAKEDA Tosio
     
    From the two-year investigation entitled "Molecular genetic analysis of mouse senile amyloidosis", we found the followings, 1. The presence of a genetic element other than molecular type of amyloid precursor protein apoA-II which modifies the development of mouse senile amyloidosis was deduced from the genetic analysis using F1, F2, and back-crossed mice between the A/J and SAM-P/1 strains of mice. 2. The progress of senescence may accelerate the development of mouse senile amyloidosis. 3. A genome mapping system using endogenous leukemia proviruses as a DNA marker has been developed for genetic analysis and positional cloning of genetic elements modifying amyloidosis. 4. Congenic strains of mice carrying amyloidogenic apoA-II (Apoa2^c) on the genetic background of SAM-R/1 with normal aging process and amyloid-resistant apoA-II (Apoa2^b) on the genetic background of SAM-P/1 with accelerated aging process were developed. 5. Using congenic strains of mice, it was revealed that (1), Apoa2^c reduced the concentration and particle size of serum high density lipoprotein, (2) Apoa2^c accelerates the development of mouse senile amyloidosis.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1990 -1992 
    Author : TAKEDA Toshio; HIGUCHI Keiichi; HOSOKAWA Masanori; AKIGCHI Ichiro; MIYAMOTO Masaomi
     
    1. Neuroaxonal dystrophic changes were observed in the nuclei fasciculi dorsalis of medulla oblongata in SAM-P/8 mice. The changes appeared earlier and progressed more rapidly in SAM-P/8 than did in SAM-R/U. beta/A4 protein-like immunoreactivity was observed in the form of granular structures(beta-LIGS) in various regions,including the medial septum, cerebral cortex, hippocampu and so on. beta-LIGS increased in number with aging, predominantly in SAM-P/8 with deficits in learning and memory. 2. The vacuolization in SAM-P/8 was marked in magnocellular reticula formation (MGRF). The severity of deficits in learning and memory closely correlated with the total area and number of vacuoles in MGRF of brain stem. Furthermore, MGRF lesioned SAM-R/1 mice showed a severe deterioration in passive avoidance tasks and an impairment in the acquisition stage of active avoidance performance. These results strongly suggest that a pathogenic role of the spongiform degeneration in brain stem in deficits in learning and memory in SAM-P/8. 3. An inbred SAM-P/10 strain has been established as a model of agerelated brain atrophy. Morphometrical studies showed that frontal cortex including prefrontal cortex, other neocortical regions, posterior piriform cortex, entorhinal cortex anterior olfactory nucleus, amygdala, and caudate putamen were atrophy-prone regions Shrinkage of the neuronal somata and loss of large neurons with age are unique for SAM-P/10, both of which bring about age-relate atrophy in cerebral cortex in SAM-P/10.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1989 -1990 
    Author : HIGUCHI Keiichi; HOSOKAWA Masanori; TAKEDA Toshio
     
    The apoA-II gene was amplified by polymerase chain reaction (PCR) from chromosomal DNA of nine inbred strains of mice. Sequence analysis of the PCR products indicated the presence of three types of apoA-II genes. Three types of apoA-II proteins (A, B and C) were predicted from the nucleotide sequence of apoA-II cDNA. Substitution of amino acid residues was noted at 4 positions. Each type was identifiable by digestion of PCR amplified apoA-II DNA, using restriction enzyme Cfr13I and MspI. The mouse strains, SAM-P/1, SAM-P/2, SJL/J, A/J had type A apoA-II. These strains generally exhibit amyloid deposition from relatively younger age. Examination of types of apoA-II and amyloid deposition in the F2 hybrid mice showed that apoA-II amyloid deposition was present only in the homozygous mice for type A apoA-II. We postulate that the molecular structure of apoA-II may be an important factor involved in the development of senile amyloidosis in mice. The expression levels of apoA-II mRNA in the liver of the SAM-P/1 strains of mice decreased rapidly with advancing age. The expression levels of apoA-II mRNA at the age of 14 months was 50 % of the level at the age of 2 months. The new system was developed for determination of amyloid fibrils specifically and kinetics of amyloid fibril polymerization was analyzed.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1989 -1990 
    Author : TAKEDA Toshio; HIGUCHI Keiichi; HOSOKAWA Masanori; HOSONO Masamichi
     
    1. The effects of age and dietary restriction on immune response were investigated using an animal model of accelerated senescence, SAM. Spleen weight and total number of splenic cells were significantly lower in the food-restricted group (fed 60% of energy intake of ad libitum fed) at 8 mo of age. Percentages of T and B cells in the splenic cells were not significantly different between the two groups. The number of direct hemolytic plaqueforming cells per 10^6 spleen cells 4 d following immunization with SRBC and DNP-Ficoll was significantly greater in the 8-mo-old mice in the food-restricted group than in the control (ad libitum fed) group. Mitogen responses to concanavalin A and LPS were maintained in the food-restricted group but were depressed in the control group at 8 mo. In addition, though autoantibody to single-stranded DNA increased in the control group with advancing age, there was a steady decrease in the food-restricted group until 8 mo. Therefore, our results suggest that when SAM are subjected to food restriction, there may be a modulatory effect on te immune dysfunction associated with advancing age. 2. After crossing with high responders, Blo. BR mice, about 12% of (Blo.BR SAM-P/1) (BRP) F_2 mice showed low responsiveness, as did SAM-P/1 mice, against two T-dependent antigens, SRBC and HRBC. Based on the incidence of the low responders in F_2 generation and statistical analyses, tehyporesponsiveness was postulated to be controlled by two genes. To survey the location of these genes, linkage analyses were performed in the F_2 mice using a large set of genetic markers. These results suggest that one of genes controlling the hyporesponsiveness of SAM-P/1 mice is linked t both Gpi-1 and c loci and that it locates at a more proximal site on Chr. /.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1987 -1988 
    Author : HOSOKAWA Masanori; HIGUCHI Keiichi; TAKEDA Toshio
     
    A new strain of mouse with late-appearing hereditary cataract was developed in the Senescence Accelerated Mouse (SAM-R/3). 1. At the beginning of selection of new strain, 5% of adult mice had cataract at least uni-laterally. During selection and brother-sister inbreeding, the incidence increased and reached 80% at generation 12. Inflammatory lesions of the cornea and eyelids began to occur later in life and theincidence was lower than that of cataract. This observation suggested to us that the cataract of this new strain was not congenital in origin but rather was age-related and did not occur consequently after the onset of inflammatory lesions around the lens tissues. The wet weight and water contents showed that the lens of this strain developed normally and that the untoward events were the result but not the cause of cataract. Urinary suger was nil in all mice examined. This cataract was not inherited in a dominant fashion with high penetrability. 2. Histologically, the mature cataract showed extreme protrusion of the lens at posterior pole and lens nucleus displaced posteriorly. The posterior lens capsule was ruptured. Degeneration of lens fiber cells and liquefaction of the cortex were also observed. Response of lens epithelial cells were not remarkable. These changes were free from inflammation of the tisses around lens. Structure of the retina was normal. The persistent hyaloid vascular system still observed in the eyes of grade 1 cataract after 5 weeks of age. This suggested to us that the persistent hyaloid vascular system may play a role in cataractogenesis but age dependency and late onset of this cataract were hardly explained by this structural anomally alone.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1986 -1988 
    Author : TAKEDA Toshio; HIGUCHI Keiichi; HOSOKAWA Masanori; SUZUKI Yasuhiro
     
    1. Sever senescece-prone series of mice(SAM-P/1,-P/2,-P/3,-P/4,-P/6,-P/7,-P/8) and 3 senescence-resistant series of mice(SAM-R/1,-R/2,-R/3) have been maintained by comtimuous sister-brother breeding in our laboratory. A steady and irreversible increase in the grading score was confirmed in both the SAM-R and SAM-P series, but more marked increase in grading score was observed in the latter than in the former. 2. During these 3 years, 2 pathologies, cataract and degenerative arthritis, were newly selected or discovered in SAM-R/3 and SAM-P/3, respectively. 3. Characteristic pathologies closely associated with senescence are senile amyloidosis in SAM-P/1 and SAM-P/2, senile cataract in SAM-P/3 and SAM-R/3, senile osteoporosis in SAM-P/6, deficits in learning and memory in SAM-P/8 and degenerative arthritis in SAM-P/3. Using these strain of mice, a number of studies on the pathogenesis of these pathologies has been conducted. 4. The mechanism of the modulatory effect on the advancement of senescence by dietary restriction was studied. It was revealed that the modulatory effect was most likely due to maintenance of immune capability and also suppresive effect on autoimmune abnormalities. 5. The murine model of accelerated senescence SAM will be a valuable tool to clarify the pathogenesis of age-related disorders and also to reveal the basic mechanism of ageing.

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