| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Ectodomain shedding is an irreversible posttranslational modification that releases the extracellular domain of membrane-anchored protein through proteolysis Ectodomain shedding of some cytokines and growth factors, such as TNF-alpha and EGF family members, converts the membrane-anchored pro-form to active soluble form. The generation of soluble TNF- alpha from membrane-bound TNF- alpha involves an enzyme activity denoted TNF- alpha converting enzyme (TACE). However, the mechanism that regulates TACE activity remains unclear. We have recently demonstrated that nardilysin (N-arginine dibasic convertase; NRDc), a metalloendopeptidase of M16 family, enhanced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF) by activation of TACE (Nishi, Hiraoka, et. al., J. Biol. Chem., 2006). NRDc binds to TACE and directly enhances the catalytic activity of TACE, which was the first description how ectodomain shedding is regulated by modulation of sheddase activi
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ty. We have also shown that NRDc enhances ectodomain shedding of several other substrates of TACE such as amyloid precursor protein (Hiraoka, et. al., J. Neurochem., 2007) and TNF- alpha (Hiraoka, et. al., BBRC, 2008), suggesting that NRDc is involved in the ectodomain shedding of a broad spectrum membrane proteins, and that it regulates various pathological processes through the enhancement of ectodomain shedding of those membrane proteins.
To clarify the biological roles of NRDc in vivo, we have recently generated NRDc-deficient mice by a targeted disruption of the NRDc gene locus. While homozygous mutant of NRDc-deficient mice were born at the expected ratio according to Mendel's law, they showed obvious pre- and past-natal growth retardation. Analysis by CT scan surprisingly showed that the volume of adipose tissue (corrected by body weight) in NRDc-deficient mice is much less than that in wild-type (WT) mice (white adipose tissue: 47% of WT, brown adipose tissue: 24% of WI). Furthermore, NRDc-deficient mice displayed significantly enhanced insulin sensitivity in a glucose tolerance test as compared to the control mice. These results suggested that NRDc plays essential roles in carbohydrate and lipid metabolisms in vivo.
Further studies on this proposal may provide a new insight for the biological and pathophysiological roles of ectodomain shedding in vivo. Less
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