Glucose-dependent Insulinotropic Peptide & Bone Turnover

葡萄糖依赖性促胰岛素肽

• 批准号: 6611821
• 负责人: CARLOS M. ISALES
• 金额: $ 29.29万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611821
• 关键词: biomarker; bone density; bone development; bone metabolism; enzyme linked immunosorbent assay; genetically modified animals; glucose receptor; hormone regulation /control mechanism; insulin; laboratory mouse; nutrition; nutrition related tag; photon absorptiometry; physiologic bone resorption; receptor expression; urinalysis

DESCRIPTION (provided by applicant): Glucose-dependent Insulinotropic Peptide (GIP) is a 42 amino acid peptide synthesized and secreted largely from endocrine cells in the small intestine. We propose that GIP modulates bone formation and resorption in response to nutrient uptake. The documented actions of GIP imply an important role in coupling food intake and absorption in the intestine with metabolic events in a number of tissues. Our observations support a role for GIP in modulating bone cell function, since GIP receptors localize to osteoblasts, osteoblast-like cells, osteoclasts, and osteocytes. Furthermore, GIP dose dependently increases intracellular cAMP and calcium contents in the osteoblast-like cell line SaOS, and stimulates alkaline phosphatase activity, collagen synthesis, and inhibits osteoclast-induced bone resorption. Based on these in vitro findings, we propose that GIP may act as a link between the nutritional state of the organism and the balance between bone formation and resorption. To evaluate further the hypothesis that GIP is anabolic for bone, we propose to define the effects of GIP on bone mass and bone turnover in vivo, both in a genetic model of GIP overexpression in transgenic mice, and in GIP receptor knock-out mouse model. As a first test of the hypothesis, GIP receptor knock-out mice will be analyzed for bone phenotypic changes, with specific reference to bone density and bone histomorphometric indices. In addition, the role of GIP-induced inhibition of osteoclastic bone resorption in the observed increases in bone mass induced by GIP will be studied in transgenic mice overexpressing GIP. These in vivo approaches are designed to test directly whether GIP can modulate bone formation and turnover. With the establishment of a genetic system, we hope to define the role of GIP in normal bone physiology. Should the in vivo findings support the profound influence of GIP on cultured osteblastoid cells, this would establish GIP as a potential link between food intake and bone metabolism. This in turn may signal GIP as a potential hormone target for pharmacologic intervention in bone pathologies such as osteoporosis.

描述（由申请人提供）：葡萄糖依赖性促胰岛素肽（GIP）是一种42个氨基酸的肽，主要由小肠内分泌细胞合成和分泌。我们认为，GIP调节骨形成和吸收的营养吸收。GIP的记录行动意味着耦合食物摄入和吸收在肠道中的代谢事件在许多组织中的重要作用。我们的观察支持GIP在调节骨细胞功能中的作用，因为GIP受体定位于成骨细胞、成骨细胞样细胞、破骨细胞和骨细胞。此外，GIP剂量依赖性地增加成骨细胞样细胞系SaOS中的细胞内cAMP和钙含量，并刺激碱性磷酸酶活性、胶原合成，并抑制破骨细胞诱导的骨吸收。基于这些体外研究结果，我们认为GIP可能是生物体营养状态与骨形成和骨吸收平衡之间的联系。为了进一步评估GIP是骨合成代谢的假设，我们建议在转基因小鼠中GIP过表达的遗传模型和GIP受体敲除小鼠模型中定义GIP对体内骨量和骨转换的影响。作为假设的第一个检验，将分析GIP受体敲除小鼠的骨表型变化，具体参考骨密度和骨组织形态计量学指数。此外，将在过表达GIP的转基因小鼠中研究GIP诱导的骨吸收抑制在观察到的GIP诱导的骨量增加中的作用。这些体内方法旨在直接测试GIP是否可以调节骨形成和转换。随着遗传系统的建立，我们希望能够确定GIP在正常骨生理中的作用。如果体内研究结果支持GIP对培养的成骨细胞的深远影响，这将建立GIP作为食物摄入和骨代谢之间的潜在联系。这反过来可能表明GIP是骨质疏松症等骨病理学药物干预的潜在激素靶点。