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

• 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
• 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

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).

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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，这些受体由鸟嘌呤核苷酸结合蛋白Gs(由GNAS基因编码)偶联，以刺激腺苷环化酶。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。该方案检测了在利用Gs蛋白作为信号转导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的表达或功能改变引起的假性甲状旁腺功能减退症1a型(PHP1a)和McCune Albright综合征，由于GNAS基因甲基化异常引起的假性甲状旁腺功能减退症1b型，以及由于钙敏感受体或甲状旁腺素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以实验室为基础的方法来阐明疾病的分子机制。具体地说，在PHP1a中，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，以确定他们是否存在继发于生长激素(GH)缺乏的生长激素分泌不足，这可能是生长激素释放激素信号转导缺陷导致的，这可能是导致身材矮小和肥胖的原因。事实上，我们已经发现这些患者中大约三分之二是生长激素缺乏(Germain-Lee等人，2003；Germain-Lee，2006；以及未发表的结果)。到目前为止，我们已经完成了对34名受试者的筛查，并在22名受试者中发现了生长激素缺乏的证据。其中一些受试者目前正在用人类重组生长激素进行生长激素治疗试验。GH治疗已经初步显示出以下一项或多项的改善：(儿童的)线性生长速度；成人的最终身高；体重参数；肥胖症；血脂谱；以及骨密度。因此，生长激素可能会改善这一患者群体的生活质量和整体健康。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(假性PHP)。假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患者有相似的表型，但那些假性PHP患者没有激素异常。这种差异是由于父系印记造成的--即，当缺陷等位基因起源于母体时，PHP1a发生继发于荷尔蒙活跃组织中特定组织印迹的荷尔蒙异常；当缺陷等位基因起源于父系时，假PHP发生时没有荷尔蒙异常。然而，假PHP患者即使不是GH缺乏，也是矮小的。PHP1a和假性PHP1a患者身高矮小的部分原因是由于G-α-S单倍体不足导致的骨痂过早融合，最有可能继发于软骨细胞的提前分化。我们目前正在研究生长激素缺乏对矮个子表型中的早期骨骺融合的影响。此外，我们计划研究生长激素在非生长激素缺乏的PHP1a患者和假性PHP1a患者(根据定义，他们不是GH缺陷)的线生长速度和最终成年身高改善中的作用。在骨骺融合之前，通过增加线性生长速度，在这些非生长激素缺乏的患者群体中，最终成人身高也有可能得到改善。传统上，人们认为假性PHP患者也是肥胖的，就像PHP1a一样。我们发现，肥胖症是PHP1a比假PHP1a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，父亲的G-α-S印记与PHP1a肥胖的发展有关(Long等人，在出版社)。