STUDIES OF HORMONE ACTION IN PATIENTS WITH ALTERED G PROTEIN FUNCTION

G 蛋白功能改变患者的激素作用研究

基本信息

批准号：
7604526
负责人：
EMILY L GERMAIN-LEE
金额：
$ 0.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2007-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7604526
关键词：
Adenylate Cyclase Adult Alleles Biochemical Biological Bone Density Calcium-Sensing Receptors Categories Cell surface Characteristics Child Chondrocytes Clinical Computer Retrieval of Information on Scientific Projects Database Defect Development Disease Endocrine Funding GNAS gene GTP-Binding Protein alpha Subunits, Gs Grant Growth Health Height Hormonal Hormone Receptor Hormones Hypoparathyroidism Institution Laboratories Lipids McCune-Albright Syndrome Methylation Molecular Morbid Obesity Mutation Obesity PTH gene Patients Phenotype Population Proteins Protocols documentation Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Quality of life Research Research Personnel Resources Role Screening procedure Secondary to Signal Transduction Signal Transduction Pathway Somatotropin Somatotropin-Releasing Hormone Source Thinking Time Tissues Transducers United States National Institutes of Health Weight base bone epiphysis growth hormone deficiency guanine nucleotide binding protein imprint improved paternal imprint protein function r-hGH-M receptor coupling treatment trial

项目摘要

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 (encoded by the GNAS gene) to stimulation of adenylyl cyclase. Expression of hormones, receptors, or Gs molecules with altered biological activity can result in gain or loss of hormone action. This 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 (PHP1a) and McCune Albright syndrome due to altered expression or function of Gs, pseudohypoparathyroidism type 1b due to abnormalities in the methylation of the GNAS gene, and hypoparathyroidism due to defects in the calcium-sensing receptor or PTH gene. Biochemical and clinical characterization of the patient's phenotype facilitates a laboratory-based approach to elucidating the molecular mechanism of disease. Specifically, within PHP1a, short stature and obesity are major clinical concerns. We have evaluated the clinical and endocrine characteristics of patients with PHP1a to determine whether they might have deficient secretion of GH secondary to growth hormone (GH) deficiency due to defective signal transduction of growth hormone-releasing hormone which could be the cause of the short stature and obesity. Indeed, we have found that approximately two-thirds of these patients are GH deficient (Germain-Lee et al., 2003; Germain-Lee, 2006; and unpublished results). At this point in time, we have completed screening of 34 subjects and have found evidence of GH deficiency in 22 subjects. Some of these subjects are currently in a GH treatment trial with human recombinant GH. GH treatment has preliminarily shown an improvement in one or more of the following: linear growth velocities (in children); final adult heights; weight parameters; adiposity; lipid profiles; and bone densities. Therefore, GH may improve the quality of life and overall health in this patient population. PHP1a is a sub-type of Albright hereditary osteodystrophy, a broader category which includes both PHP1a and pseudopseudohypoparathyroidism (pseudoPHP). PseudoPHP results from the same heterozygous inactivating mutations in the GNAS gene which cause PHP1a. Although patients with PHP1a and pseudoPHP have similar phenotypes, those with pseudoPHP do not have hormonal abnormalities. This difference occurs because of paternal imprinting-- ie, when the defective allele is maternal in origin, PHP1a occurs with hormonal abnormalities secondary to tissue-specific imprinting in hormonally active tissues; when the defective allele is paternal in origin, pseudoPHP occurs without hormonal abnormalities. However, pseudoPHP patients are also short even though they are not GH deficient. The short stature in both PHP1a and pseudoPHP is partially contributed to by premature fusion of the epiphyses most likely secondary to premature chondrocyte differentiation due to haploinsufficiency of G-alpha-s. We are currently investigating the impact of GH deficiency versus the premature epiphyseal fusion in the short stature phenotype. In addition, we plan to investigate the role of GH in the improvement of linear growth velocity and final adult height of those patients with PHP1a who are not GH deficient as well as patients with pseudoPHP (who, by definition, are not GH deficient). It is possible that by increasing linear growth velocity prior to epiphyseal fusion, final adult heights could be improved in these non-GH deficient patient populations as well. Classically, it has been thought that pseudoPHP patients are also obese, as in PHP1a. We have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings implicate paternal imprinting of G-alpha-s in the development of the obesity in PHP1a (Long et al, in press).

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。许多激素的作用需要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（由 GNAS 基因编码）耦合来刺激腺苷酸环化酶。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强或丧失。该协议检查利用 Gs 蛋白作为信号转导器的信号转导途径中激素作用改变的分子基础。这些疾病包括由于 Gs 表达或功能改变引起的 1a 型假性甲状旁腺功能减退症 (PHP1a) 和 McCune Albright 综合征、由于 GNAS 基因甲基化异常引起的 1b 型假性甲状旁腺功能减退症，以及由于钙敏感受体或 PTH 基因缺陷引起的甲状旁腺功能减退症。患者表型的生化和临床特征有助于采用基于实验室的方法来阐明疾病的分子机制。具体来说，在 PHP1a 中，身材矮小和肥胖是主要的临床问题。我们评估了 PHP1a 患者的临床和内分泌特征，以确定他们是否可能因生长激素释放激素信号转导缺陷而继发生长激素 (GH) 缺乏，从而导致身材矮小和肥胖。事实上，我们发现这些患者中大约三分之二存在 GH 缺乏（Germain-Lee 等人，2003 年；Germain-Lee，2006 年；以及未发表的结果）。目前，我们已经完成了 34 名受试者的筛查，并在 22 名受试者中发现了 GH 缺乏的证据。其中一些受试者目前正在进行人类重组 GH 的 GH 治疗试验。 GH 治疗初步显示出以下一项或多项方面的改善：线性生长速度（儿童）；最终成年身高；重量参数；肥胖;血脂谱；和骨密度。因此，GH 可以改善该患者群体的生活质量和整体健康状况。 PHP1a 是奥尔布赖特遗传性骨营养不良症的一个亚型，这是一个更广泛的类别，包括 PHP1a 和假性甲状旁腺功能减退症 (pseudoPHP)。伪 PHP 是由导致 PHP1a 的 GNAS 基因中相同的杂合失活突变引起的。尽管 PHP1a 和假性 PHP 患者具有相似的表型，但假性 PHP 患者没有激素异常。这种差异的发生是由于父本印记——即，当有缺陷的等位基因起源于母本时，PHP1a 会出现继发于激素活性组织中的组织特异性印记的激素异常；当有缺陷的等位基因起源于父系时，会出现假性PHP，而不会出现激素异常。然而，假性 PHP 患者虽然不缺乏 GH，但身材也很矮。 PHP1a和pseudoPHP的身材矮小部分是由于骨骺过早融合造成的，很可能是由于G-α-s单倍体不足导致软骨细胞过早分化所致。我们目前正在研究 GH 缺乏与骨骺过早融合对身材矮小表型的影响。此外，我们计划研究 GH 在改善那些不缺乏 GH 的 PHP1a 患者以及伪 PHP 患者（根据定义，不缺乏 GH ）的线性生长速度和最终成年身高方面的作用。通过在骨骺融合前增加线性生长速度，这些非生长激素缺乏的患者群体的最终成年身高也可能得到改善。传统上，人们认为伪 PHP 患者也肥胖，就像 PHP1a 一样。我们发现，与pseudoPHP相比，肥胖是PHP1a中更突出的特征，并且严重肥胖是PHP1a的具体特征。这些发现表明 G-α-s 的父系印记在 PHP1a 肥胖的发展中（Long 等人，出版中）。