Modeling Bone Formation and 1,25 Vitamin D in Humoral Hypercalcemia of Malignancy

恶性肿瘤体液高钙血症中骨形成和 1,25 维生素 D 的建模

• 批准号: 7650170
• 负责人: ANDREW F. STEWART
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650170
• 关键词: Bone Resorption; Characteristics; Continuous Infusion; Coupling; Hand; Hour; Human; Human Volunteers; Hypercalcemia of Malignancy; Hyperparathyroidism; Infusion procedures; Injection of therapeutic agent; Kidney; Lead; Learning; Mixed Function Oxygenases; Modeling; Osteoblasts; Osteogenesis; Plasma; Regulation; Signal Transduction; Syndrome; Vitamin D; comparative; design; human subject; parathyroid hormone-related protein; receptor; response; skeletal

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.

描述（由申请人提供）：恶性肿瘤的体液性高钙血症（HHM）和原发性甲状旁腺功能亢进（HPT）在许多方面彼此相似，并且这些相似性自20世纪80年代后期PTHrP的发现以来已经变得明显。另一方面，两种综合征之间仍存在两个未解决的谜一样的差异：HPT与成骨细胞活性增加和血浆1，25（OH）2D增加相关，而HHM与相反相关。这是令人惊讶的，因为目前的教条表明，PTH和PTHrP信号类似地通过共同的PTH 1受体。最近，我们在健康人受试者中进行了两到四天的PTH和PTHrP的直接比较输注，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，与预期的对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PTH和PTHrP通过PTH 1 R在人肾脏中信号传导的方式是不相同的。其次，尽管HPT的特征性骨形成增加，并且尽管每天间歇注射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抑制。这些观察结果强调了一个事实，即我们有很多要了解PTH和PTHrP如何调节骨形成和骨吸收。因此，本提案的具体目标是： 1.确定PTH和PTHrP给药的时间曲线如何影响人体合成代谢骨骼反应 2.确定长期连续或脉冲式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长期（两周）持续的PTH或PTHrP输注研究，旨在阐明PTH和PTHrP的合成代谢作用的机制，并充分定义PTH 1 R偶联肾脏1-α羟化酶的明显差异。