| Project/Area Number |
12671087
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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 | Kobe University |
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Principal Investigator |
SUGIMOTO Toshitsugu Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (00226458)
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| Co-Investigator(Kenkyū-buntansha) |
CHIHARA Kazuo Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00107955)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Calcium-sensing receptor / Parathyroid / Bone / Parathyroid hormone / Proliferation / Vitamin D receptor / Polymorphism / Hyperparathyroidism / 家族性低カルシウム尿性高カルシウム血症 / 原発性副甲状腺機能亢進症 / 続発性副甲状腺機能亢進症 / 骨リモデリング |
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| Research Abstract |
The down-regulation of both calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) in parathyroid (PT) glands of secondary hyperparathyroidism (HPT) caused by chronic renal failure has been associated with parathyroid hormone (PTH) hypersecretion as well as PT hypergrowth. The present study was performed to clarify the predominance of decreased CaSr and VDR in the high proliferative activity of PT glands. We obtained evidence that the decrease in CaSR expression is associated with the high proliferative activity of PT glands in secondary HPT, independently of the decreased VDR. Similar relationship was also observed in primary HPT. We also reported two cases of familial hypocalciuric hypercalcemia whose parathyroid glands were enlarged. Analysis of DNA sequence and receptor function revealed inactivated multations of CaSR (R220W, R648stop). Moreover, in primary culture of human parathyroid cells, high concentration of calcium as well as CaSR agonists inhibited PT proliferation. T
… More
he present findings indicate an important role of CaSR in the regulation of PT proliferation as well as PTH secretion. Primary and secondary HPT are heterogeneous diseases in the clinical course and severity. We raised the hypothesis that CaSR polymorphisms might be associated with the magnitude of PTH secretion and the clinical severity of primary and secondary HPT. In the present study, we analyzed the relationship between CaSR polymorphisms and biochemical markers. The present study is the first to show that CaSR polymorphisms in both codon 990 and intron 4 were closely associated with themagnitude of PTH secretion and thus the clinical severity in primary and secondary HPT patients. These polymorphisms would partly exsplain the heterogeneity of pathological severity in these diseases. As for bone, we demonstrated that both p42/44 and p38 MAP kinase cascades play pivotal roles in CaSR-stimulated mitogenic responses. Moreover, we also obtained data indicating a functional role of CaSR in the regulation of osteoblast function. Less
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