MENTORED ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

建议(改编自申请者的摘要)：有一个非常特别的 慢性肾功能衰竭患者心血管发病率和死亡率较高。胰岛素 抵抗力、血脂异常和高血压形成了一系列危险因素 出现在这些患者身上。这些风险因素之间可能存在联系。 这会使肾功能衰竭患者心血管加速 疾病(CVD)。这个应用程序的目标是测试监管失调 胰岛素介导的NEFA抑制与增强的A1- 中度慢性肾衰患者的肾上腺素能受体血管反应性。在……里面 为了实现这一目标，将在以下方面实现具体目标 中度慢性肾脏疾病患者：1)测定血浆NEFA 血药浓度和胰岛素介导的NEFA周转；2)测定A1-肾上腺素能 受体血管反应性；以及3)决定升高和 降低NEFAs对A1肾上腺素能受体血管反应性的影响。结果是 这些针对中度CRF患者的研究将与血压正常的患者进行比较。 肾功能正常的高血压对照组。首先，NEFA将是 使用两级高胰岛素血症前后的测量 正血糖钳。随后，基线A1-肾上腺素能受体血管 反应性将通过确定加压敏感度来衡量 苯肾上腺素，一种选择性A1肾上腺素能受体激动剂。为了评估 NEFAs对血管反应性、升压敏感性的影响 在NEFAs升高后，通过输注 肝素脂内注射和通过输注烟酸减少NEFAs， 并与基线升压反应进行比较。如果NEFA调节A1-肾上腺素能 受体血管反应性，那么候选者将决定 胰岛素增敏剂曲格列酮对NEFAs和A1-肾上腺素能的影响 受体血管反应性。提出的研究对定义 肾功能衰竭患者的血脂异常可能与高血压有关 在这群人中。这项研究可能会为潜在的 心血管危险因素、血脂异常、胰岛素抵抗之间的联系 还有高血压。此外，这项研究应该为以下工作奠定基础 旨在预防高海拔地区血管疾病的新治疗策略 有心血管风险的患者。

PROPOSAL (Adapted from the applicant's abstract): There is an extraordinarily high cardiovascular morbidity and mortality in patients with CRF. Insulin resistance, dyslipidemia and hypertension form a cluster of risk factors present in these patients. There may be a link between these risk factors which predisposes patients with renal failure to accelerated cardiovascular disease (CVD). The goal of this application is to test whether dysregulation of insulin-mediated suppression of NEFA is associated with enhanced A1- adrenergic receptor vascular reactivity in patients with moderate CRF. In order to accomplish this goal, the following specific aims will be pursued in patients with moderate chronic renal disease: 1) determine plasma NEFA concentrations and insulin-mediated NEFA turnover; 2) determine A1-adrenergic receptor vascular reactivity; and 3) determine the effects of raising and lowering NEFAs on A1-adrenergic receptor vascular reactivity. The results of these studies in patients with moderate CRF will be compared to normotensive and hypertensive controls with normal renal function. First, NEFAs will be measured before and after utilization of a two-stage hyperinsulinemic euglycemic clamp. Subsequently, baseline A1-adrenergic receptor vascular reactivity will be measured by determining pressor sensitivity to phenylephrine, a selective A1-adrenergic receptor agonist. In order to assess the effect of NEFAs on vascular reactivity, pressor sensitivity to phenylephrine will be measured after elevation of NEFAs via infusion of intralipid with heparin and reduction of NEFAs via infusion of nicotinic acid, and compared to baseline pressor responses. If NEFAs modulate A1-adrenergic receptor vascular reactivity, then the candidate will determine the effects of the insulin-sensitizing agent, troglitazone, on NEFAs and A1-adrenergic receptor vascular reactivity. The research proposed is critical in defining lipid abnormalities in renal failure which may be associated with hypertension in this population. This research may provide further support for a potential link between the cardiovascular risk factors, dyslipidemia, insulin resistance and hypertension. In addition, this research should lay the groundwork for new treatment strategies aimed to prevent vascular disease in the high cardiovascular risk patients.