PTH/PTHRP RECEPTOR DEFECTS IN PSEUDOHYPOPARATHYROIDISM

假性甲状旁腺功能减退症（PHP）是一组疾病， 以甲状旁腺激素抵抗为特征;患者表现为低钙血症， 高磷血症和甲状旁腺激素水平升高。 确定这些患者的 在分子水平上的缺陷提供了巨大的见解， PTH发挥作用的机制。 患有PHP Ia的患者减少了 激活其受体-腺苷酸环化酶（AC）效应系统， PTH和其他激素以及发育/骨骼缺陷（Albright's 遗传性骨营养不良（AHO））。 一般来说，这些患者 缺乏或有缺陷的G-α-s-亚基，尽管这不是 普遍的。 激素抵抗可能是因为 G-α-s，但这种生化病变和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，并且通常在同一家族中， PHP Ia患者 一个额外的缺陷已被假定，因为 G-α-s缺陷似乎不足以解释所有的临床 表现。 PHP Ib患者具有孤立的PTH抵抗， 正常的身体外观和无G-α-s异常;这些患者 最有可能有受体缺陷，尽管它们也是一种异质性的， 人口 我们最近克隆了cDNA和编码人类 结合PTH和PTHrP的受体。 当这个受体被激活时 通过PTH或PTHrP的氨基末端类似物，它通过 至少两种效应物，AC和磷脂酶C。我们建议确定 PTH/PTHrP受体结构和功能特性及其 这些基因导致这些患者的疾病。 我们首先将 正常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 受体mRNA/基因缺陷，最初集中在PHP Ib（目标2）。 一旦突变受体被确定，我们将描述其特征。 在多种生物测定中的生物学特性（目的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，但将提供深入了解 PTH和PTHrP的作用机制。 这些知识，特别是 PTH/PTHrP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.