MODELING BONE FORMATION & 1,25 VITAMIN D IN HUMORAL HYPERCALCEMIA OF MALIGNANCY

描述(申请人提供)：恶性体液性高钙血症和原发性甲状旁腺功能亢进症在许多方面有相似之处，自上世纪80年代末S发现甲状旁腺功能亢进症以来，这些相似之处已经很明显。另一方面，两个综合征之间仍有两个未解之谜：恶性高钙血症与成骨细胞活性增加和血浆1，25(OH)2D升高有关，而甲状旁腺功能亢进与相反相关。这是令人惊讶的，因为目前的教义表明，PTH和PTHrP都通过共同的PTH1受体发出类似的信号。最近，我们在健康受试者中进行了两到四天的PTH和PTHrP的直接对比输注，以评估正常健康受试者成骨细胞骨形成和1，25(OH)2D的调节作用。这些研究取得了令人惊讶的观察结果：首先，与预期的1，25(OH)2D的等效效应相反，稳态、连续注入PTH和PTHrP对1，25(OH)2D产生的影响截然不同。提示人肾组织中PTH和PTHrP通过PTH1R传递信号的方式不同。第二，尽管甲状旁腺素和甲状旁腺素每日间歇注射可促进骨形成，但甲状旁腺素和甲状旁腺素同时滴注48-96小时会显著抑制健康志愿者的骨形成。这些观察结果强调了这样一个事实，即我们对甲状旁腺素和甲状旁腺素如何调节骨形成和骨吸收有很多需要了解的地方。因此，目前这项建议的具体目标是： 1.确定甲状旁腺素和甲状旁腺素给药的时间分布如何影响人类的合成代谢骨骼反应 2.确定长期持续或搏动性的甲状旁腺素和/或甲状旁腺素受体对人体血浆1，25(OH)2D调节的影响。 这些研究将是人类甲状旁腺素或甲状旁腺素rP输注的第一次长期(两周)研究，旨在阐明甲状旁腺素和甲状旁腺素rP合成代谢作用的机制，并充分确定甲状旁腺素1R与肾脏1-α羟基酶偶联的明显差异。

DESCRIPTION (provided by applicant): Humoral hypercalcemia of malignancy (HHM) and primary hyperparathyroidism (HPT) resemble one another n many ways, and these similarities have been apparent since the discovery of PTHrP in the late 1980's. On the other hand, two unresolved enigmatic differences remain between the two syndromes: HPT is associated with increases in osteoblast activity and increases in plasma 1,25(OH)2D, whereas HHM is associated with the reverse. This is surprising, because current dogma indicates that both PTH and PTHrP signal similarly via the common PTH1 receptor. Recently, we have performed directly comparative infusions of PTH and PTHrP in healthy human subjects over two to four days to evaluate the regulation of osteoblastic bone formation and 1,25(OH)2D in normal healthy subjects. These studies make surprising observations: First, in contrast to the anticipated equivalent effects on 1,25(OH)2D, steady-state, continuous infusions of PTH and PTHrP produce very different effects on 1,25(OH)2D. This suggests that the manner in which PTH and PTHrP signal via the PTH1R in human kidney is not identical. Second, despite the increase in bone formation characteristic of HPT, and despite the increase in bone formation induced by intermittent daily injections of PTH and PTHrP, 48-96 hour infusion of both PTH and PTHrP lead to marked suppression of bone formation in healthy human volunteers. These observations highlight the fact that we have much to learn about how PTH and PTHrP regulate bone formation and bone resorption. The Specific Aims of the current proposal are therefore: 1. To define how the temporal profile of PTH and PTHrP administration influences the anabolic skeletal response in humans 2. To determine how long-term continuous or pulsatile PTH and/or PTHrP influences plasma 1,25(OH)2D regulation in humans. These studies will be the first long-term (two week) sustained PTH or PTHrP infusion studies in humans, and are designed to elucidate the mechanisms of the mechanisms underlying the anabolic effects of PTH and PTHrP, and to fully define the apparent differences in PTH1R coupling to renal 1-alpha hydroxylase.