2004 Fiscal Year Final Research Report Summary
Molecular mechanisms of skin aging in klotho-deficient mouse.
| Project/Area Number |
14570810
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Fukuoka University |
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Principal Investigator |
FURUMURA Minao Fukuoka University, Hospital, Instructor, 病院, 講師 (10315070)
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| Project Period (FY) |
2002 – 2004
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| Keywords | skin / aging / vitamin D3 / gene expression / DIPCA.3 |
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| Research Abstract |
The klotho-deficient mouse is a unique short lifespan mouse strain in which a single gene mutation causes multiple aging-related disorders. Aging-suppressor klotho protein is thought to be important in molecular regulation of age-related disorders, as well as aging symptoms. The klotho-deficient mouse is an excellent animal model for skin aging since it shows similar symptoms to aging human skin, such as accelerated thinning of the skin, decreased in hair follicles, and the disappearance of subcutaneous fat tissue. In human, the association of klotho gene polymorphism with common age-related changes has been reported, suggesting that this gene may also be involved in the etiology of human age-related diseases including aging symptoms of the skin. To identify differentially expressed genes, we performed comprehensive gene expression analyses of klotho-deficient mouse skin using a combination of membrane cDNA arrays, glass cDNA microarrays, and plastic/glass oligo microarrays. Comparisons of data from several different microarray experiments were related to their common reference sequence using the UniGene gene database. Among differentially expressed genes, a number of already discovered 'age-related' were identified in addition to genes modulated by elevated 1,25-(OH)2D. A number of transcription factor SP1- regulated genes such as interleukins, elastin, and transcription factor OCT1 were demonstrated to be down-regulated, suggesting their involvement in the aging-suppresser signal activated by klotho protein. Suppression of SP1 activity in the klotho-deficient mouse skin was confirmed by ELISA assays for detecting DNA-protein interactions. Suppression of SP1 appears to be a downstream event resulting from elevated 1,25-(OH)2D, since 1,25-(OH)2D induces VDUP1 over-expression that suppresses the thioredoxin function which is required for SP1 activation.
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