HORMONAL CONTROL OF RENAL 1,25(OH)2D3 BIOSYNTHESIS

描述（改编自申请人的摘要）： 拟议研究的目标是扩大目前的知识， 激素和离子调节哺乳动物的细胞机制 肾近曲小管合成1，25-二羟维生素D3 （1，25（OH）2D3）。1，25（OH）2D 3是肠道Ca的主要调节剂， 磷吸收。1，25（OH）2D 3的合成在生命周期中变化， 生长期增加，老年期减少，以满足骨钙 P的要求。骨矿物质需求与肾功能的整合 1，25（OH）2D 3的合成仍然未知，但甲状旁腺激素（PTH）， 胰岛素样生长因子I（IGF-1）和低磷饮食（LPD）是主要的 肾线粒体25-羟基维生素D3-1的公认刺激物 α羟化酶（1-OHase）。 在近端小管中，PTH激活 cAMP/cAMP依赖性蛋白激酶（PKA）和磷脂酶C (PLC)/蛋白激酶C（PKC）信号系统。 虽然无论是系统 可介导PTH对1-OHase的作用，PTH激活PKC， 1，25（OH）2D 3在相同的生理浓度，而更大 cAMP/PKA活化需要一定浓度的PTH。 的 IGF-1和LPD刺激1-OHase的机制尚不清楚，但 IGF-1可促进PTH和LPD对1-OHase的反应。 本申请提出测试以下总体假设： PLC/PKC系统介导PTH激活1-OHase， 和/或肾旁分泌IGF-1在PTH期间放大1-OHase活性， 洛杉矶警局 将通过以下具体目的对假设进行检验：1） 确定参与急性和慢性PTH的PKC亚型 刺激大鼠近端小管1，25（OH）2D 3产生; 2） 确定PTH、IGF-1和LPD是否产生净1，25（OH）2D 3 结果从相互刺激的1-OH酶和抑制24- OHase活性; 3）探讨IGF-1 刺激近端小管1-OHase活性;和4）使用来自 通过上述研究，探讨还原1，25（OH）2D 3的机制 生产过程中老化。 拟议的研究旨在提高对以下问题的认识： 1，25（OH）2D 3和缺陷1，25（OH）D3生产的生理控制 在衰老和骨质流失和骨折的疾病，如 骨质疏松症和原发性甲状旁腺功能亢进症。

DESCRIPTION (Adapted from the Applicant's Abstract): The long-term objectives of the proposed research are to expand present knowledge of the cellular mechanisms whereby hormones and ions regulate mammalian renal proximal tubule synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 1,25(OH)2D3 is the major regulator of intestinal Ca and P absorption. 1,25(OH)2D3 synthesis varies during the life-cycle, increasing during growth and decreasing in the elderly, to meet bone Ca and P requirements. Integration of bone mineral requirements and renal 1,25(OH)2D3 synthesis remains unknown, but parathyroid hormone (PTH), insulin-like growth factor I (IGF-1) and low P diet (LPD) are major recognized stimuli of the renal mitochondrial 25-hydroxyvitamin D3-1 alpha hydroxylase (1-OHase). In proximal tubules, PTH activates both the cAMP/cAMP-dependent protein kinase (PKA) and the phospholipase C (PLC)/protein kinase C (PKC) signalling systems. Although either system could mediate PTH action on 1-OHase, PTH activates PKC and stimulates 1,25(OH)2D3 at the same physiologic concentration, whereas greater concentrations of PTH are required for cAMP/PKA activation. The mechanism whereby IGF-1 and LPD stimulate 1-OHase remains unknown, but IGF-1 may facilitate 1-OHase response to PTH and LPD. The current application proposes to test the overall hypotheses that the PLC/PKC system mediates PTH activation of 1-OHase and that systemic and/or renal paracrine IGF-1 amplifies 1-OHase activity during PTH and LPD. The hypotheses will be tested by the following Specific Aims: 1) to identify the PKC isoforms involved in acute and chronic PTH stimulation of rat proximal tubule 1,25(OH)2D3 production; 2) to determine whether net 1,25(OH)2D3 production by PTH, IGF-1 and LPD results from reciprocal stimulation of 1-OHase and suppression of 24- OHase activities; 3) to explore potential mechanisms whereby IGF-1 stimulates proximal tubule 1-OHase activity; and 4) using knowledge from the above studies, to investigate the mechanism for reduced 1,25(OH)2D3 production during aging. The proposed studies are intended to improve the understanding of physiologic control of 1,25(OH)2D3 and defective 1,25(OH)D3 production during aging and diseases of bone loss and fracture, such as osteoporosis and primary hyperparathyroidism.