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

描述（由申请人提供）：恶性肿瘤体液高钙血症（HHM）和原发性甲状旁腺功能亢进症（HPT）在许多方面彼此相似，并且自 20 世纪 80 年代末发现 PTHrP 以来，这些相似性就已经很明显了。另一方面，这两种综合征之间仍然存在两个未解决的神秘差异：HPT 与成骨细胞活性增加和血浆 1,25(OH)2D 增加相关，而 HHM 则与相反相关。这是令人惊讶的，因为当前的教条表明 PTH 和 PTHrP 都通过共同的 PTH1 受体发出类似的信号。最近，我们在健康人类受试者中进行了两到四天的直接比较 PTH 和 PTHrP 输注，以评估正常健康受试者中成骨细胞骨形成和 1,25(OH)2D 的调节。这些研究得出了令人惊讶的观察结果：首先，与预期对 1,25(OH)2D 的等效作用相反，稳态、连续输注 PTH 和 PTHrP 对 1,25(OH)2D 产生非常不同的作用。这表明人肾中 PTH 和 PTHrP 通过 PTH1R 发出信号的方式并不相同。其次，尽管HPT具有骨形成增加的特征，并且尽管每天间歇性注射PTH和PTHrP诱导骨形成增加，但48-96小时输注PTH和PTHrP会导致健康人类志愿者的骨形成明显受到抑制。这些观察结果强调了这样一个事实：关于 PTH 和 PTHrP 如何调节骨形成和骨吸收，我们还有很多东西需要了解。因此，当前提案的具体目标是： 1. 定义 PTH 和 PTHrP 给药的时间曲线如何影响人类的合成代谢骨骼反应 2. 确定长期连续或脉动 PTH 和/或 PTHrP 如何影响人体血浆 1,25(OH)2D 调节。 这些研究将是第一个针对人类的长期（两周）持续 PTH 或 PTHrP 输注研究，旨在阐明 PTH 和 PTHrP 合成代谢作用的潜在机制，并全面定义 PTH1R 与肾 1-α 羟化酶偶联的明显差异。

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.