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

• 批准号: 8549199
• 负责人: MURAT BASTEPE
• 金额: $ 36.04万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/8549199
• 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

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(申请人提供)：G？S对甲状旁腺素和甲状旁腺素的作用至关重要。编码G？S(GNAS)的基因也产生XL？S，它在包括成骨细胞和肾脏细胞在内的各种组织中表达。XL？S可以模仿G？S，通过刺激cAMP的产生来回应甲状旁腺素，尽管它也被预测有独特的作用。在几种人类疾病中发现了GNAS突变，这些疾病损害了通过PTH/PTHrP受体(PTHR)传递的信号。这些突变大多同时影响G？S和XL？S。对小鼠和人类的研究表明，XL？S在生理和人类疾病中发挥重要作用，但XL？S的作用尚不清楚。我们最近的研究为XL？S的细胞作用提供了新的见解，结合我们在XL？S基因敲除小鼠中的发现，我们假设XL？S对体内钙磷代谢的调节是必要的。在当前建议的目标1中，我们将讨论在出生后早期发育过程中，肾小管甲状旁腺激素介导的作用是否需要S。我们将确定a)XLKO小鼠甲状旁腺激素的近端小管作用是否受损，以及b)XLKO小鼠的PTH耐药表型是否通过转基因重组XL？S在近端小管的表达来挽救。在目标2中，我们将研究XLKO是否允许甲状旁腺素在肾近端小管持续作用，这可以解释XLKO小鼠甲状旁腺素抵抗的表型。因此，我们将确定a)PTHR在XLKO小鼠近端小管的内化是否得到增强；b)具有持续活性的突变的PTHR能否挽救XLKO小鼠的PTH耐药表型；或者通过在近端小管过表达G？S来挽救PTH耐药表型；以及c)XL？S与动力素的相互作用是否影响PTH的作用。这些研究将对PTH和XL？S在肾脏近端小管中的作用提供新的见解，并将适用于这些蛋白在肾脏中的作用。 骨骼组织。我们的结果还将有助于揭示XL？S在其他系统中的作用 提高我们对GNAS突变引起疾病的潜在机制的了解。鉴于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。