Aldosterone and Diabetic Cardiovascular Disease: Research and Mentoring Progam

描述（由申请人提供）：摘要本K24申请旨在为以下受保护的时间提供支持：1）指导/教学初级临床研究者; 2）调查醛固酮在糖尿病心血管疾病病理生理学中的作用的以患者为导向的研究。最近的数据提供了支持的假设，盐皮质激素受体（MR）的激活有助于糖尿病血管损伤，虽然机制是不确定的。与这一假设一致，我们的临床前研究表明，阻断MR可减少糖尿病db/db小鼠的肾损伤，并减少高血压血管紧张素II（ANGII）输注啮齿动物的血管炎症和心脏及肾损伤。我们的临床研究表明，在接受血管紧张素转换酶（ACE）抑制治疗的糖尿病受试者中，与氢氯噻嗪（HCTZ）治疗相比，MR拮抗剂依普利酮短期治疗可改善冠状动脉循环功能。该观察结果不能归因于血压变化，表明MR拮抗剂不是通过经典的肾脏效应发挥作用，而是通过额外的非容量控制依赖性机制发挥作用。该提案检验了以下假设：MR激活有助于接受ACE抑制剂治疗的2型糖尿病（T2 DM）受试者的血管疾病进展，因此，MR拮抗剂通过减少血管功能障碍和损伤、抑制ANGII血管效应、改善冠状动脉循环和心脏功能以及改善肾血管功能发挥有益作用。为了解决这些假设，我们将对接受慢性ACE抑制剂治疗的T2 DM和高血压受试者进行一项前瞻性双盲研究，随机接受以下三种治疗之一：1）MR拮抗剂螺内酯; 2）HCTZ加钾;和3）安慰剂。这些研究提供了一个肥沃的领域调查感兴趣的学员以患者为导向的研究，并将提供新的信息的机制，MR拮抗剂减少糖尿病心血管损伤，目的是引入新的，有效的治疗糖尿病患者心血管损伤。 公共卫生相关性：该拨款申请旨在支持对糖尿病和心脏病患者进行研究感兴趣的新一代医生和研究人员的培训和指导。糖尿病导致血管损伤。这种损伤会导致许多健康问题，包括心脏病、肾衰竭和中风。这项研究的目的是确定阻断一种称为醛固酮的激素的作用是否能改善2型糖尿病患者心脏和肾脏的血管功能，以及这是否能改善心脏和肾脏功能。因此，这项研究可能会为糖尿病患者及其心脏和肾脏损伤带来新的治疗方法，并将为指导以患者为导向的研究的学员提供论坛。

DESCRIPTION (provided by applicant): ABSTRACT This K24 application is to provide support for protected time for: 1) mentoring/teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone in the pathophysiology of diabetic cardiovascular disease. Recent data provide support for the hypothesis that activation of the mineralocorticoid receptor (MR) contributes to diabetic vascular injury, though the mechanisms are uncertain. Consistent with this hypothesis, our pre-clinical studies demonstrate that blockade of MR reduces renal injury in diabetic db/db mice and reduces vascular inflammation and cardiac and renal injury in hypertensive, angiotensin II (ANGII)-infused rodents. Our clinical studies show that short-term treatment with the MR antagonist eplerenone improves coronary circulatory function as compared to treatment with hydrochlorothiazide (HCTZ) in subjects with diabetes receiving angiotensin-converting enzyme (ACE) inhibition therapy. This observation could not be attributed to blood pressure changes suggesting that MR antagonists are not working via a classical renal effect, but via an additional, volume control-independent mechanism. This proposal tests the hypotheses that MR activation contributes to progression of vascular disease in subjects with type 2 diabetes mellitus (T2DM) receiving ACE inhibitor therapy, and consequently, MR antagonists exert beneficial effects by reducing vascular dysfunction and injury, inhibiting ANGII vascular effects, improving coronary circulatory and cardiac function and improving renovascular function. To address these hypotheses we will perform a prospective double-blind study in subjects with T2DM and hypertension receiving chronic ACE inhibitor therapy randomized to one of three treatments: 1) MR antagonist spironolactone; 2) HCTZ plus potassium; and 3) placebo. These studies provide a fertile area for investigation by trainees interested in patient-oriented research and will provide new information about the mechanisms by which MR antagonists reduce diabetic cardiovascular injury, with the goal of introducing new, effective treatments of cardiovascular injury in individuals with diabetes. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This grant application seeks support for the training and mentoring of a new generation of physicians and investigators interested in performing research in patients with diabetes and heart disease. Diabetes causes injury to blood vessels. This injury leads to many health problems including heart disease, kidney failure and stroke. The goal of this research is to determine whether blocking the actions of a hormone known as aldosterone improves the function of vessels in the hearts and kidneys of patients with type 2 diabetes and whether this leads to improvements in heart and kidney function. Thus, this research may lead to new treatments for patients with diabetes and injury to their hearts and kidneys, and will provide a forum for mentoring trainees in patient-oriented research.