Aldosterone and Diabetic Cardiovascular Disease: Research and Mentoring Progam

描述(由申请人提供)摘要本K24申请旨在为以下方面的保护时间提供支持：1)初级临床研究人员的指导/教学；2)以患者为导向的研究，调查醛固酮在糖尿病心血管疾病的病理生理学中的作用。最近的数据支持这一假说，即盐皮质激素受体(MR)的激活有助于糖尿病血管损伤，尽管机制尚不确定。与这一假设一致，我们的临床前研究表明，阻断MR可以减少糖尿病db/db小鼠的肾脏损伤，并减少高血压、血管紧张素II(AngII)注射的啮齿动物的血管炎症和心脏和肾脏损伤。我们的临床研究表明，在接受血管紧张素转换酶(ACE)抑制治疗的糖尿病患者中，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脉循环功能。这种观察结果不能归因于血压变化，这表明MR拮抗剂不是通过经典的肾脏效应发挥作用，而是通过一种额外的、不依赖于容量控制的机制发挥作用。这项建议验证了这样的假设：在接受ACE抑制剂治疗的2型糖尿病患者中，MR激活有助于血管病变的进展，因此，MR拮抗剂通过减少血管功能障碍和损伤，抑制血管效应，改善冠脉循环和心脏功能，改善肾血管功能，发挥有益的作用。为了解决这些假设，我们将在接受慢性ACE抑制剂治疗的T2 DM和高血压患者中进行一项前瞻性双盲研究，随机分为三种治疗之一：1)MR拮抗剂螺内酯；2)HCTZ+钾；以及3)安慰剂。这些研究为对以患者为中心的研究感兴趣的受训者提供了一个肥沃的研究领域，并将提供有关MR拮抗剂减少糖尿病心血管损伤的机制的新信息，目的是为糖尿病患者引入新的有效的心血管损伤治疗方法。 公共卫生相关性：项目描述这一赠款申请寻求支持培训和指导新一代对糖尿病和心脏病患者进行研究感兴趣的医生和研究人员。糖尿病会对血管造成损伤。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名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，以及这是否会改善心脏和肾脏功能。因此，这项研究可能会为糖尿病和心脏和肾脏损伤的患者带来新的治疗方法，并将为指导受训者进行以患者为导向的研究提供一个论坛。

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.