XLas Relative to Gsa in Bone and Mineral Ion Metabolism

XLas 在骨和矿物质离子代谢中相对于 Gsa

基本信息

批准号：
8675845
负责人：
MURAT BASTEPE
金额：
$ 37.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675845
关键词：
25-hydroxyvitamin D Ablation Address Adult Affect Animals Biological Process Calvaria Cell Line Cell membrane Cells Clinical Cyclic AMP Data Development Dihydroxycholecalciferols Disease Dynamin Embryo Employee Strikes Exons G-substrate GTP-Binding Proteins Generations Genes Goals Health Hormones Human Hypocalcemia result Injection of therapeutic agent Ions Kidney Knockout Mice Knowledge Lead Learning Life Measures Mediating Messenger RNA Metabolism Minerals Mixed Function Oxygenases Mus Mutant Strains Mice Mutation N-terminal Parathyroid Hormone Receptor Parathyroid gland Pathogenesis Patients Phenotype Phosphorylation Physiology Play Proteins Proximal Kidney Tubules Pseudohypoparathyroidism Receptor Signaling Regulation Relative (related person)Resistance Role Serum Signal Pathway Signal Transduction Skeletal Development Skeletal system System Testing Tissues Transgenic Mice Tubular formation Variant analog bone calcium metabolism design human disease improved in vivo inorganic phosphate insight kidney cell mouse model mutant novel overexpression parathyroid hormone-related protein phosphorus metabolism postnatal promoter pup receptor internalization reconstitution response reuptake skeletal tissue tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): G¿s is critical for the actions of PTH and PTHrP. The gene encoding G¿s (GNAS) also gives rise to XL¿s, which is expressed in various tissues including osteoblastic and renal cells. XL¿s can mimic G¿s by stimulating cAMP generation in response PTH, although it is also predicted to have unique actions. Mutations in GNAS are found in several human diseases that impair signaling through the PTH/PTHrP receptor (PTHR). Most of these mutations affect both G¿s and XL¿s. Studies in mice and humans indicate that XL¿s plays important roles in physiology and human disease, but the actions of XL¿s remain poorly understood. Our recent studies have provided novel insights into the cellular actions of XL¿s, and together with our findings obtained from XL¿s knockout (XLKO) mice, these led us to hypothesize that XL¿s is necessary for the regulation of calcium and phosphorus metabolism in vivo. In Aim 1 of the current proposal, we will address whether XL¿s is necessary for PTH-mediated actions in the renal proximal tubule during early postnatal development. We will determine a) whether proximal tubular actions of PTH in XLKO mice are impaired and b) whether the PTH resistance phenotype in XLKO mice is rescued by transgenically reconstituting XL¿s expression in the proximal tubule. In Aim 2, we will address whether XL¿s allows PTH actions to be sustained in the renal proximal tubule, which could explain the PTH resistance phenotype in XLKO mice. We will thus determine a) whether PTHR internalization is enhanced in the proximal tubule of XLKO mice; b) whether the PTH resistance phenotype in XLKO mice can be rescued by a mutant PTHR with sustained activity or by overexpressing G¿s in the proximal tubule; and c) whether the interaction of XL¿s with dynamin influences PTH actions. These studies will provide novel insights into the actions of PTH and XL¿s in the renal proximal tubule, and these will be applicable to the actions of these proteins in skeletal tissues. Our results will also help reveal the roles of XL¿s in other systems, in addition to improving our knowledge of the mechanisms underlying the diseases caused by GNAS mutations. Given that XL¿s can activate the ubiquitous cAMP signaling pathway, our results will likely have even broader implications for human health and disease.

描述（由申请人提供）：G¿ s 对于 PTH 和 PTHrP 的作用至关重要编码 G¿ 的基因。 s (GNAS) 也会产生 XL¿ s，在多种组织中表达，包括成骨细胞和肾细胞。 s 可以模仿 G¿通过刺激 cAMP 的生成来响应 PTH，尽管 GNAS 中的突变也被发现在几种损害通过 PTH/PTHrP 受体 (PTHR) 的信号传导的人类疾病中。 s 和 XL¿ s. 对小鼠和人类的研究表明 XL¿ s 在生理学和人类疾病中发挥着重要作用，但 XL¿我们最近的研究对 XL 的细胞作用提供了新的见解。 s，以及我们从 XL 获得的发现s 基因敲除 (XLKO) 小鼠，这些导致我们追逐 XL¿ s 对于体内钙和磷代谢的调节是必要的在当前提案的目标 1 中，我们将解决 XL¿在出生后早期发育过程中，s 对于肾近端小管中 PTH 介导的作用是必需的。我们将确定 a) XLKO 小鼠中 PTH 的近端肾小管作用是否受损，b) XLKO 小鼠中的 PTH 抗性表型是否可以通过转基因重建来挽救。 XL??在目标 2 中，我们将讨论 XL¿ 是否表达。 s 允许 PTH 作用在肾近曲小管中持续，这可以解释 XLKO 小鼠中的 PTH 抵抗表型，因此我们将确定 a) PTHR 内化是否在 XLKO 小鼠的近曲小管中增强；b) PTH 抵抗表型是否增强。在 XLKO 小鼠中，可以通过具有持续活性的突变 PTHR 或通过过度表达 G¿ s 在近曲小管中；c) XL¿ 是否相互作用这些研究将为 PTH 和 XL 的作用提供新的见解。肾近曲小管中的蛋白质，这些将适用于这些蛋白质在我们的结果也将有助于揭示 XL 的作用。另外，在其他系统中提高我们对 GNAS 突变引起的疾病机制的了解。 s 可以激活无处不在的 cAMP 信号通路，我们的结果可能会对人类健康和疾病产生更广泛的影响。