CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

囊性纤维化跨膜电导调节器

• 批准号: 7604604
• 负责人: Garry R Cutting
• 金额: $ 0.04万
• 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/7604604
• 关键词: Address; Adenylate Cyclase; Adrenergic Agents; Affect; Agonist; Cell membrane; Characteristics; Chloride Ion; Chlorides; Chronic Sinusitis; Clinical; Computer Retrieval of Information on Scientific Projects Database; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Disease; Epithelial; Epithelial Cells; Event; Exocrine pancreatic insufficiency; Facies; Family; Family member; Funding; Future; GNAS gene; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genotype; Grant; Heterotrimeric G Protein Subunit; Hormones; Institution; Intestinal Obstruction; Kidney; Link; Lung diseases; Male Infertility; Mediating; Mutation; Nasal Epithelium; Obesity; Parathyroid Hormones; Pathway interactions; Patients; Phenotype; Phosphorylation; Pseudohypoparathyroidism; RNA; Regulation; Research; Research Personnel; Resistance; Resources; Role; Severity of illness; Signal Transduction; Skin; Source; Therapeutic; Tissues; United States National Institutes of Health; Variant; adrenergic; body system; cellular targeting; computerized data processing; cystic fibrosis patients; hormone resistance; human PTH protein; in vivo; interest; receptor; response; subcutaneous

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. Cystic Fibrosis is (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the primary chloride (Cl-) channel in epithelial cells of numerous organ systems. In CF patients, a severe reduction in Cl- transport across epithelial cell membranes results in obstructive pulmonary disease, chronic sinusitis, pancreatic insufficiency, intestinal obstruction, and male infertility. While genotype-phenotype correlations have shown that some of the variablility in clinical presentation is due to specific mutations in CFTR, extreme variability exists among patients with identical mutations suggesting factors other than CFTR genotype may contribute to disease severity. Genes regulating normal CFTR function via upstream signaling events are rational candidate modifiers of CF. Upstream regulation of CFTR is cAMP dependent, and recent studies have shown CFTR mediated Cl- transport is modulated through phosphorylation by cyclic AMP (cAMP)-dependent protein kinase A. In epithelial cells cAMP levels are influenced by extra-cellular agonists via G-protein coupled transmembrane receptors. Thus, CFTR activity can be affected by G-protein coupled signaling processes that activate adenylyl cyclase and which generate cAMP. We are interested in investigating the role of genes in this upstream activation pathway in modulating the function of CFTR, and in turn disease severity. To this end, we propose to study CFTR function in patients with severe alterations in genes involved in this pathway. Patients with Albright's Hereditary Osteodystrophy (AHO) have been shown to have decreased cAMP levels in response to beta-adrenergic stimulation. Over the last decade this has been shown to be due to mutations in GNAS1, the gene that encodes the stimulatory alpha subunit of heterotrimeric G proteins (Gs-alpha). Patients with mutations in GNAS1 have a characteristic physical phenotype including short stature, brachydactyly, obesity, rounded facies, and subcutaneous ossifications. A subset of these patients also have hormone resistance, classically defined as decreased renal response to parathyroid hormone, but many patients have also been documented to have resistance to other hormones that signal via Gs-alpha. The exact mechanism for this hormone resistance is unclear, as patients within the same family and carrying the same mutation in GNAS1 can have variable phenotypes with regard to hormone resistance. We have preliminary data on one patient with AHO who has a decreased CFTR response to beta-agonists in the nasal epithelia and the skin. This suggests a link between altered Gs-alpha function and decreased CFTR function. To better understand the role of the cAMP-dependent pathway in modulating CFTR function, we propose to characterize CFTR function in patients with AHO. By examining GNAS1 RNA levels and cAMP levels in epithelial tissues, we will define the expected level of flux through the cAMP dependent pathway. CFTR function will then be assessed in these same tissues. The results of this study will define the role of the cAMP-dependent pathway in CFTR function, which may guide future therapeutic options for patients with CF. It may also address the mechanism of hormone resistance in AHO patients since it will be the first study directly characterizing, in vivo, the effects of GNAS1 mutation on one of its cellular targets. Results from family members will aid in genotype-phenotype correlations in AHO and clarify functional defects from familial variation.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 囊性纤维化是（CF）是由囊性纤维化跨膜电导调节剂（CFTR）突变引起的常染色体隐性膜疾病，这是众多器官系统上皮细胞中的一氯化物（CL-）通道。 在CF患者中，跨上皮细胞膜的CL转运严重降低会导致阻塞性肺部疾病，慢性鼻窦炎，胰腺功能不全，肠梗阻和不孕症。 尽管基因型 - 表型相关性表明，临床表现中的某些可变性是由于CFTR的特异性突变引起的，但具有相同突变的患者之间存在极端变异性，表明CFTR基因型以外的其他因素可能导致疾病严重程度。 通过上游信号事件调节正常CFTR功能的基因是CF的有理候选修饰符。 CFTR的上游调节是cAMP依赖性的，最近的研究表明，CFTR介导的Cl-转运是通过环状AMP（CAMP）依赖性蛋白激酶A通过磷酸化来调节的。在上皮细胞中，cAMP的cAMP水平受到细胞外激动剂的影响，受到G蛋白酶摄取的透膜甲虫受体的影响。 因此，CFTR活性可能会受到激活腺苷环酶并产生CAMP的G蛋白耦合信号传导过程的影响。 我们有兴趣研究基因在调节CFTR功能以及疾病严重程度的该上游激活途径中的作用。 为此，我们建议研究该途径涉及的基因严重改变的患者的CFTR功能。 奥尔布赖特（Albright）的遗传性骨营养不良（AHO）的患者已显示出对β-肾上腺素能刺激的cAMP水平降低。 在过去的十年中，这已被证明是由于GNAS1突变引起的，GNAS1是编码异三聚体G蛋白（GS-Alpha）刺激性α亚基的基因。 GNAS1中突变的患者具有特征性的物理表型，包括身材矮小，腕足，肥胖，圆形相和皮下骨性。 这些患者的一部分也具有激素耐药性，通常定义为对甲状旁腺激素的肾脏反应降低，但也已记录了许多患者对通过GS-Alpha发出信号的其他激素的抗性。这种激素抗性的确切机制尚不清楚，因为同一家族中的患者并在GNAS1中携带相同的突变可以在激素耐药性方面具有可变的表型。 我们拥有一名AHO患者的初步数据，该患者对鼻上皮和皮肤的CFTR反应降低了。 这表明改变的GS-Alpha函数与CFTR功能降低之间存在联系。 为了更好地了解CAMP依赖性途径在调节CFTR功能中的作用，我们建议表征AHO患者的CFTR功能。 通过检查上皮组织中的GNAS1 RNA水平和cAMP水平，我们将定义通过cAMP依赖途径的预期通量水平。 然后将在这些相同的组织中评估CFTR功能。 这项研究的结果将定义依赖CAMP的途径在CFTR功能中的作用，这可能指导CF患者的未来治疗选择。 它还可以解决AHO患者激素耐药性的机理，因为它将是第一个直接表征GNAS1突变对其细胞靶标之一的影响。 家庭成员的结果将有助于AHO中的基因型 - 表型相关性，并阐明家族变异的功能缺陷。