Gene-by-Gene Interactions and Lung Fluid Balance in Patients with Heart Failure

心力衰竭患者的基因间相互作用和肺液平衡

• 批准号: 8792926
• 负责人: ERIC M SNYDER
• 金额: $ 47.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792926
• 关键词: Gene; Interactions; Lung; Fluid; Balance

DESCRIPTION (provided by applicant): Decompensated heart failure challenges the ability of the lungs to maintain fluid homeostasis and can result in alveolar flooding and death; however, not all patients with decompensated heart failure develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic influence on susceptibility to pulmonary edema in this population. In the lungs, alveolar Na+ and fluid clearance are primarily regulated by the activity of epithelial Na+ channels (ENaC). The activity and number of ENaCs are regulated by ¿2 adrenergic receptors (ADRB2s). Stimulation of the ADRB2s by an endogenous (epinephrine) or exogenous agonist increases alveolar fluid clearance. Therefore, there are three key proteins involved in alveolar fluid clearance: ADRB2s, ENaCs, and epinephrine. There are common functional variants in the genes that encode the ADRB2, the alpha subunit of the ENaC, and phenylethanolamine N- methyltransferase (PNMT, which converts norepinephrine to epinephrine). It remains unclear what effects of these genes will be on patients with heart failure. Our long term goal is to determine appropriate therapeutic interventions for improving ion and lung fluid regulation in disease based on genetic information. The objective in this proposal is to determine the influence of genetic variation on lung Na+ and fluid handling, which is likely to have significant clinical applications, particularly in patients with heart failure who have an elevated adrenergic drive. Our central hypothesis is that genetic variation of the ADRB2, ENaC, and PNMT will influence baseline lung fluid and lung fluid clearance in response to a ¿-agonist. The rationale for the proposed research is that determining how these genes regulate lung fluid in heart failure will allow for personalization of current therapy as well as utilization of alternative therapies to reduce the susceptibility of pulmonary edema in heart failure. This proposal is significant because we will explore the therapeutic effects of stimulation of the ¿2-adrenergic receptors on lung fluid balance, and how genetic variation can influence this therapeutic response. This will add to the understanding of specific therapies used to reduce the risk of pulmonary edema in patients with HF. The research proposed is innovative because we will be testing the influence of genetic variation of ADRB2, ENaC and PNMT (which have not been explored together in patients with HF) on lung ion and fluid regulation in HF, we are determining how multiple genes interact together to influence lung fluid balance in patients with HF, and, finally, we have recently developed a new technique to assess lung ion and fluid changes which we will couple with existing methods to expand techniques that can be used to assess changes in lung water.

描述（由申请人提供）：失代偿性心力衰竭挑战肺部维持液体稳态的能力，并可能导致肺泡充盈和死亡；然而，尽管临床特征相似，但并非所有失代偿性心力衰竭患者都会出现肺水肿，这表明存在遗传因素。对该人群肺水肿易感性的影响 在肺部，肺泡 Na+ 和液体清除率主要受上皮 Na+ 通道活性的调节。 (ENaC) 的活性和数量受 ¿ 2 肾上腺素能受体 (ADRB2) 内源性（肾上腺素）或外源性激动剂刺激 ADRB2 会增加肺泡液清除率，因此，参与肺泡液清除率的有 3 个关键蛋白：ADRB2s、ENaCs 和肾上腺素。存在于编码 ADRB2、ENaC 的 α 亚基和苯乙醇胺 N-甲基转移酶的基因中（PNMT，将去甲肾上腺素转化为肾上腺素）目前尚不清楚这些基因对心力衰竭患者有何影响，我们的长期目标是根据遗传信息确定适当的治疗干预措施，以改善疾病中的离子和肺液调节。本提案的目的是确定遗传变异对肺 Na+ 和液体处理的影响，这可能具有重要的临床应用，特别是对于肾上腺素能驱动力升高的心力衰竭患者。这ADRB2、ENaC 和 PNMT 将影响基线肺液和肺液清除率，以响应 ¿拟议研究的基本原理是，确定这些基因如何调节心力衰竭中的肺液将允许当前治疗的个体化以及利用替代疗法来降低心力衰竭中肺水肿的易感性。因为我们将探索刺激的治疗效果 ¿ 2-肾上腺素能受体对肺液平衡的影响，以及遗传变异如何影响这种治疗反应，这将增加对用于降低心力衰竭患者肺水肿风险的特定疗法的理解。测试 ADRB2、ENaC 和 PNMT 的遗传变异（尚未在心力衰竭患者中一起探索）对心力衰竭患者肺离子和液体调节的影响，我们正在确定多个基因如何相互作用来影响心力衰竭患者的肺液体平衡心力衰竭，最后，我们最近开发了一种评估肺离子和液体变化的新技术，我们将其与现有方法结合起来，以扩展可用于评估肺水变化的技术。