| Project/Area Number |
13671149
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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 |
Endocrinology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
FUKUMOTO Seiji The University of Tokyo, Department of Medicine, Lecturer, 医学部附属病院, 講師 (30202287)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEUCHI Yasuhiro The University of Tokyo, Department of Medicine, Research Associate, 医学部附属病院, 助手 (50202164)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | calcium-sensing receptor / Hypocalcemia / Hypercalcemia / mutation |
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| Research Abstract |
Calcium-sensing receptor (CaSR) is a member of G protein-coupled receptors that has been identified as a essential molecular for regulating secretion of parathyroid hormone (PTH). Extracellular Ca inhibits secretion of PTH through CaSR and there is a strict negative feedback system between serum Ca and PTH secretion. It has been already known that heterozygous inactivating mutations of CaSR result in familial hypocalciuric hypercalcemia (FHH) characterized by relative hypocalciuria and mild hypercalcemia, whereas heterozygous activating mutations of CaSR cause autosomal dominant hypocalcemia (ADH) with relative hypercalciuria and PTH-deficient hypocalcemia. However, the histology of parathyroid glands in patients with FHH has not been reported although clinical features of FHH are similar to those of patients with primary hyperparathyroidism, which is the typical cause of hypercalcemia. In addition, detailed clinical features of patients with AMD have been unknown, either. By examining mutations in CaSR gene and analyzing functional properties of mutant CaSRs in vitro, we have demonstrated that parathyroid glands in patients with FHH show distinct histological features called lipohyperplasia, which are different from those of patients with primary hyperparathyroidism. In addition, we have shown that some activating mutations of CaSR with severe activation cause Bartter-like syndrome by inhibiting renal outer medullary potassium channel in thick ascending limb of Henle. These results indicate the variability of clinical manifestations caused by mutations in CaSR gene and seem to have contributed to the establishment of the new classification of derangements in calcium metabolism based on molecular mechanisms.
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