STUDIES OF HORMONE ACTION IN PATIENTS WITH ALTERED G PROTEIN FUNCTION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。许多激素的作用需要它们与特定的细胞表面受体相互作用，这些受体通过鸟嘌呤核苷酸结合蛋白Gs偶联以刺激腺苷酸环化酶。生物活性改变的激素、受体或Gs分子的表达可导致激素作用的增加或减少。该方案研究了利用Gs蛋白作为信号换能器的信号转导途径中激素作用改变的分子基础。这些疾病包括由Gs表达或功能改变引起的1a型假性甲状旁腺功能低下和McCune Albright综合征，由钙敏感受体或PTH基因缺陷引起的甲状旁腺功能低下，以及由生长激素释放激素受体缺陷引起的身材矮小。患者表型的生化和临床特征有助于以实验室为基础的方法来阐明疾病的分子机制。我们评估了1a型PHP患者的临床和内分泌特征，以确定他们是否可能有生长激素（GH）分泌不足。我们现在已经完成了26名受试者的筛查，并在19名受试者中发现生长激素缺乏的证据。这些受试者是我们用人重组生长激素替代激素的亚研究试验的候选对象。GH治疗已初步显示在以下一个或多个方面有改善：身高速度、BMI、脂质谱和骨密度。生长激素缺乏可能在这些研究对象中常见的肥胖和身材矮小中起作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The action of many hormones requires their interaction with specific cell surface receptors that are coupled by the guanine nucleotide-binding protein Gs to stimulation of adenylyl cyclase. Expression of hormones, receptors, or Gs molecules with altered biological activity can result in gain or loss of hormone actionThis protocol examines the molecular basis for altered hormone action in signal transduction pathways that utilize Gs protein as a signal transducer. These disorders include pseudohypoparathyroidism type 1a and McCune Albright syndrome due to altered expression or function of Gs, hypoparathyroidism due to defects in the calcium-sensing receptor or PTH gene, and short stature due to defects in the growth hormone-releasing hormone receptor. Biochemical and clinical characterization of the patient's phenotype facilitates a laboratory-based approach to elucidating the molecular mechanism of disease. We have evaluated the clinical and endocrine characteristics of patients with PHP type 1a to determine whether they might have deficient secretion of growth hormone (GH). We have now completed screening of 26 subjects, and have found evidence of GH deficiency in 19 subjects. These subjects are candidates for our substudy trial of hormone replacement with human recombinant GH. GH treatment has preliminarily shown an improvement in one or more of the following: height velocity, BMI, lipid profiles, and bone densities. GH deficiency may play a role in the obesity and short stature that is common in these subjects.