PTH/PTHRP RECEPTOR DEFECTS IN PSEUDOHYPOPARATHYROIDISM

假性甲状旁腺功能减退症(PHP)是一组疾病，所有这些疾病都 以甲状旁腺素抵抗为特征；患者表现为低钙血症， 高磷血症和甲状旁腺素水平升高。定义这些患者的 分子水平上的缺陷为我们提供了对 甲状旁腺素的作用机制。感染新城疫Ia的患者减少了 其受体-腺苷环化酶(AC)效应系统的激活 甲状旁腺激素和其他激素，以及发育/骨骼缺陷(奥尔布赖特病 遗传性骨病(Aho))。通常，这些患者都有 G-α-S亚基缺陷或缺陷，尽管这不是 万能的。激素抵抗可能是由异常的 G-阿尔法-S，但这种生化损伤和AHO之间的联系是 不清楚。假性PHP患者没有激素抵抗，尽管 他们有AHO和G-α-S缺陷，经常是同一个家族的人 与PHIa患者在一起。另一个缺陷被认为是因为 G-α-S缺陷似乎不足以解释所有的临床 表现形式。PHIb患者有孤立的甲状旁腺激素耐药， 体征正常，无G-α-S异常； 最有可能的是受体缺陷，尽管它们也是异质性的 人口。我们最近克隆了cdna和编码一个人的基因 结合PTH和PTHrP的受体。当这个受体被激活时 通过甲状旁腺素或甲状旁腺素的氨基末端类似物，它通过AT 至少两种效应物，AC和磷脂酶C。我们建议确定 甲状旁腺素/甲状旁腺素rP受体(S)的结构和功能特性及其意义 导致这些患者患病的基因(S)。我们首先会 正常受体和受体特性的完整表征 其基因(Aim 1)。然后我们将使用几种方法来确定 PHP中的受体mRNA/基因缺陷，最初集中在PHP Ib(目标2)。 一旦鉴定出突变受体，我们将确定它们的特征 多种生物检测中的生物学特性(目标3)。确定 这些患者的受体缺陷不仅有助于了解 这些相关疾病的病理生理学，但将提供对 甲状旁腺素和甲状旁腺素的作用机制。这一知识，尤其是 甲状旁腺素/甲状旁腺素受体系统在骨骼中的作用，可能导致 更合理地干预骨骼疾病，包括骨丢失状态。

Pseudohypoparathyroidism (PHP) is a group of disorders all of which are characterized by PTH resistance; patients manifest hypocalcemia, hyperphosphatemia, and elevated PTH levels. Defining these patients' deficiencies at the molecular level has provided enormous insights into mechanisms by which PTH acts. Patients with PHP Ia have diminished activation of their receptor-adenylate cyclase (AC) effector system by PTH and other hormones, and developmental/skeletal defects (Albright's Hereditary Osteodystrophy (AHO)). Commonly, these patients have deficient or defective G-alpha-s-subunits, although this is not universal. Hormonal resistance probably is explained by the abnormal G-alpha-s, but the link between this biochemical lesion and AHO is unclear. Patients with pseudo-PHP have no hormonal resistance, although they have AHO and G-alpha-s defects, and often are in the same family with PHP Ia patients. An additional defect has been postulated because the G-alpha-s defects appear insufficient to account for all the clinical manifestations. PHP Ib patients have isolated PTH resistance, with normal physical appearance and no G-alpha-s abnormality; these patients most likely have receptor defects, although they too are a heterogeneous population. We have recently cloned cDNA and the gene encoding a human receptor that binds both PTH and PTHrP. When this receptor is activated by either amino-terminal analogs of PTH or PTHrP, it signals through at least two effectors, AC and phospholipase C. We propose to determine the structural and functional properties of PTH/PTHrP receptor(s) and their gene(s) that contribute to disease in these patients. We first will complete characterization of the properties of the normal receptor and its gene (Aim 1). We then will use several approaches to determine the receptor mRNA/gene defects in PHP, initially focusing on PHP Ib (Aim 2). Once mutant receptors are identified, we will characterize their biological properties in multiple bioassays (Aim 3). Determining receptor defects in these patients will not only help to understand the pathophysiology of these related diseases, but will provide insight into the mechanisms of action of PTH and PTHrP. This knowledge, particularly of the role of the PTH/PTHrP receptor system in the skeleton, may lead to more rational intervention in bone diseases, including bone-loss states.