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: 8803402
• 负责人: ERIC M SNYDER
• 金额: $ 44.24万
• 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/8803402
• 关键词: ADRB2 gene; Admission activity; Adrenergic Agents; Adrenergic Receptor; Agonist; Alternative Therapies; Alveolar; Alveolar Cell; Award; Breathing; Cessation of life; Characteristics; Clinical; Clinical Research; Code; Development; Disease; Elderly; Epinephrine; Equilibrium; Excision; Floods; Fluid Balance; Future; Genes; Genetic; Genetic Variation; Goals; Heart failure; Homeostasis; Hospitals; Human; Individual; Ions; Knowledge; Laboratories; Liquid substance; Lung; Mediating; Methods; Mission; Norepinephrine; Outcome; Patients; Persons; Phenylethanolamine N-Methyltransferase; Population; Predisposition; Proteins; Public Health; Pulmonary Edema; Regulation; Research; Risk; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Translating; United States; United States National Institutes of Health; Variant; Water; adrenergic; apical membrane; base; clinical application; clinical practice; epithelial Na+ channel; gene interaction; gene therapy; genetic information; improved; innovation; response

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 ß2 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 ß-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 ß2-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（由适用提供）：不足的心力衰竭挑战肺保持液体稳态的能力，并可能导致Alloolar洪水和死亡；但是，并非所有具有代偿性心力衰竭的患者都会发展出肺水肿，这是理想的类似临床特征，这表明对该人群中对肺水肿的易感性产生了遗传影响。在肺中，肺泡Na+和流体清除率主要受上皮Na+通道（ENAC）的活性调节。 ENAC的活性和数量受ß2肾上腺素受体（ADRB2S）调节。通过内源性（肾上腺素）或外源性激动剂来刺激ADRB2会增加全动物流体清除率。因此，猫液清除率涉及三个关键蛋白：ADRB2S，ENAC和肾上腺素。在编码ADRB2，ENAC的α亚基和苯甲基胺N-甲基转移酶（PNMT）（PNMT）的基因中，有常见的功能变体（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的影响。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。该提案的目的是确定遗传变异对肺NA+和液体处理的影响，它可能具有重要的临床应用，尤其是在心力衰竭肾上腺素驱动升高的患者中。我们的中心假设是，ADRB2，ENAC和PNMT的遗传变异将影响基线肺液和肺液清除，以响应ß-激动剂。拟议研究的理由是，确定这些基因如何调节心力衰竭的肺液将允许个性化当前疗法以及利用替代疗法以降低肺水肿对心力衰竭的敏感性。该建议很重要，因为我们将探讨β2-肾上腺素受体刺激对肺液平衡的治疗作用，以及遗传变异如何影响这一理论反应。这将增加对降低HF患者肺水肿风险的特定疗法的理解。提出的研究具有创新性，因为我们将测试ADRB2，ENAC和PNMT的遗传变异的影响（在HF患者中尚未一起探索的HF患者）对HF中的肺和液体调节的影响，我们正在确定多个基因之间的相互作用如何相互作用以在HF患者中影响肺部的肺液位，我们将如何与新技术相互作用，我们最近将Lung In Inique IIN跨越，我们将跨越了lung iif，我们将跨越我们，我们将逐渐地进行培养。可用于评估肺水变化的技术。