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; 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 A主要源自胃的肽以活性（酰化）和非活性（DES-酰化）形式存在于血浆中。生长素的主要活性形式含有28种具有独特后翻译后修饰的氨基酸：Ser3的羟基由辛酸酯化。 N-八链酰基基团对于GH（生长激素）释放活性至关重要。血浆生长素素在能量稳态，食物摄入量以及可能在GH释放和肥胖症中发挥作用。迄今为止，尚不清楚如何调节流循环的生长素素水平。该应用的总体假设是葡萄糖，胰岛素和胰岛素敏感性在生长素蛋白的急性调节中起作用。还将研究年龄和BMI对循环生长素对这些因素反应的影响。 具体目的1。确定葡萄糖（外围或腔内）和/或外围胰岛素的短期调节在多大程度上是介导的。在人类中，葡萄糖给药后循环蛋白水平降低。目前尚不清楚葡萄糖给药的途径在多大程度上在其对循环生长素蛋白的影响中起作用。胰岛素对在葡萄糖疾病下的胰岛素作用的研究已经产生不一致的结果，即循环生长素蛋白与无变化的降低。尚不清楚葡萄糖给药的途径在多大程度上在其对循环血清蛋白的影响以及胰岛素抵抗的差异是否对胰岛素和/或葡萄糖对循环胡质蛋白的影响产生影响。在两组BMI匹配具有不同胰岛素耐药性的年轻人中，我们将检查胰岛素条件下胰岛素对外周生长素的影响，并将其与口服和IV葡萄糖的作用进行比较。我们还将比较口服和IV葡萄糖对外周生长素蛋白的影响。静脉输送后达到的葡萄糖水平将与口服葡萄糖测试期间达到的葡萄糖水平相匹配。胰岛素和葡萄糖对生物活性生长素蛋白的影响尚未报道。使用在我们的实验室中开发的测定，将测量生物活性和非活性生长素释放蛋白。 具体目的2。确定胰岛素介导的循环血清素水平的降低是否取决于年龄。胰岛素灵敏度随着年龄的增长而降低。这部分是由于年龄依赖性腹部内脏脂肪增加的结果。提出的研究将研究年轻人和老年人在急性胰岛素介导的循环生长素蛋白（生物活性，非活性形式）水平上是否存在差异。