MODELING BONE FORMATION AND 125 VITAMIN D IN HUMORAL HYPERCALCEMIA OF MALIGNANCY

恶性肿瘤体液性高钙血症中骨形成和 125 维生素 D 的建模

• 批准号: 7139533
• 负责人: ANDREW F. STEWART
• 金额: $ 29.25万
• 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/7139533
• 关键词: 1,25 dihydroxycholecalciferol; bone metabolism; clinical research; hormone regulation /control mechanism; human subject; hypercalcemia; osteoblasts; osteogenesis; parathyroid hormone related protein; parathyroid hormones; vitamin metabolism

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（HHM）和原发性甲状旁腺功能亢进症（HPT）的体液高钙血症（HPT）彼此相似，并且自1980年代后期发现PTHRP以来，这些相似之处已经显而易见。另一方面，两种综合症之间仍然存在两个未解决的神秘差异：HPT与成骨细胞活性的增加有关，血浆1,25（OH）2D的增加，而HHM与反向相关。这是令人惊讶的，因为当前的教条表明PTH和PTHRP信号都通过公共PTH1受体类似。最近，我们在两到四天的健康受试者中直接对健康受试者进行了PTH和PTHRP的比较输注，以评估正常健康受试者中成骨细胞骨形成的调节和1,25（OH）2D。这些研究令人惊讶地观察：首先，与预期的对1,25（OH）2D，稳态的，PTH和PTHRP的连续输注的等效作用相反，对1,25（OH）2d产生了截然不同的影响。这表明人肾脏中PTH和PTHRP信号通过PTH1R信号的方式并不相同。其次，尽管HPT的骨形成特征增加，尽管每天间歇性地注射PTH和PTHRP引起的骨形成增加，但在健康人类志愿者中，PTH和PTHRP的48-96小时输注PTH和PTHRP导致了明显的抑制骨形成。这些观察结果强调了一个事实，即我们有很多关于PTH和PTHRP如何调节骨形成和骨吸收的事实。因此，当前提案的具体目的是： 1。定义PTH和PTHRP给药的时间分布如何影响人类的合成代谢骨骼反应 2。确定长期连续或脉冲PTH和/或PTHRP如何影响血浆1,25（OH）2D调节。 这些研究将是人类中的第一长期（两周）持续的PTH或PTHRP输注研究，旨在阐明PTH和PTHRP合成代谢作用的机制的机制，以充分定义PTH1R偶联到肾脏1-α羟基羟基酶的明显差异。