MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

以患者为导向的研究职业发展奖

• 批准号: 7124305
• 负责人: RALF M NASS
• 金额: $ 13.13万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124305
• 关键词: MENTORED; PATIENT; ORIENTED; RESEARCH; CAREER

DESCRIPTION (provided by applicant): Ghrelin a peptide which is mainly derived from the stomach, is present in plasma in an active (acylated) and inactive (des-acylated) form. The major active form of ghrelin contains 28 amino acids with a unique post-translational modification: the hydroxyl group of ser3 is esterified by octanoic acid. The n-octanoyl group is essential for the GH (growth hormone) releasing activity. Plasma ghrelin plays a role in energy homeostasis, food intake, and possibly in GH release and obesity. To date it is unclear how circulating ghrelin levels are regulated. The overall hypothesis of this application is that glucose, insulin as well as insulin sensitivity play a role in the acute regulation of ghrelin. The influence of age and BMI on the response of circulating ghrelin to these factors will also be examined. Specific Aim 1. To determine to what extent the short-term regulation of ghrelin is mediated through glucose (peripheral or luminal) and/or peripheral insulin. In man, circulating ghrelin levels decrease after glucose administration. It is unclear to what extent the route of glucose administration plays a role in its effects on circulating ghrelin. Studies of insulin effects on ghrelin levels under euglycemic conditions have yielded inconsistent results, i.e., a decrease in circulating ghrelin vs. no change. It is also unclear to what extent the route of glucose administration plays a role in its effects on circulating ghrelin and whether differences in insulin resistance have an impact on the effects of insulin and/or glucose on circulating ghrelin. In two groups of BMI matched young adults with different insulin resistance, we will examine the effects of insulin under euglycemic conditions on peripheral ghrelin and compare them with the effects of oral and IV glucose. We will also compare the effects of oral and IV glucose on peripheral ghrelin with each other. The glucose levels reached after IV administration will match those reached during the oral glucose test. The effects of insulin and glucose on bioactive ghrelin have not been reported. Using assays developed in our laboratory, both bioactive and inactive ghrelin will be measured. Specific Aim 2. To determine whether the insulin-mediated decrease in circulating ghrelin levels is age dependent. Insulin sensitivity decreases with age. This is partially a result of the age-dependent increase in abdominal visceral fat. The studies proposed will investigate whether there are differences between young and older adults regarding the acute insulin mediated decrease in circulating ghrelin (bioactive, inactive form) levels.

描述（由申请人提供）： Ghrelin是一种主要来源于胃的肽，以活性（酰化）和非活性（去酰化）形式存在于血浆中。生长激素释放肽的主要活性形式包含28个氨基酸，具有独特的翻译后修饰：ser 3的羟基被辛酸酯化。正辛酰基对于GH（生长激素）释放活性是必需的。血浆ghrelin在能量稳态、食物摄入中起作用，并且可能在GH释放和肥胖中起作用。到目前为止，还不清楚循环ghrelin水平是如何调节的。本申请的总体假设是葡萄糖、胰岛素以及胰岛素敏感性在生长激素释放肽的急性调节中起作用。还将检查年龄和BMI对循环胃饥饿素对这些因素反应的影响。 具体目标1。确定ghrelin的短期调节在多大程度上是通过葡萄糖（外周或管腔）和/或外周胰岛素介导的。在人类中，循环ghrelin水平在葡萄糖给药后降低。目前尚不清楚葡萄糖给药途径在多大程度上影响其对循环胃饥饿素的影响。在血糖正常条件下胰岛素对胃饥饿素水平影响的研究产生了不一致的结果，即，循环胃饥饿素的减少与没有变化。目前还不清楚葡萄糖给药途径在多大程度上影响其对循环胃饥饿素的作用，以及胰岛素抵抗的差异是否会影响胰岛素和/或葡萄糖对循环胃饥饿素的作用。在两组BMI匹配的具有不同胰岛素抵抗的年轻人中，我们将检查正常血糖条件下胰岛素对外周ghrelin的影响，并将其与口服和IV葡萄糖的影响进行比较。我们还将比较口服和静脉注射葡萄糖对外周ghrelin的影响。IV给药后达到的葡萄糖水平将与口服葡萄糖试验期间达到的水平相匹配。胰岛素和葡萄糖对具有生物活性的ghrelin的影响尚未见报道。使用我们实验室开发的测定法，将测量生物活性和非活性ghrelin。 具体目标2。确定胰岛素介导的循环ghrelin水平降低是否具有年龄依赖性。胰岛素敏感性随着年龄的增长而下降。这部分是由于腹部内脏脂肪的年龄依赖性增加。拟议的研究将调查年轻人和老年人之间是否存在关于急性胰岛素介导的循环ghrelin（生物活性，非活性形式）水平降低的差异。