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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

基本信息

批准号：
8997520
负责人：
ERIC M SNYDER
金额：
$ 38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997520
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 apical membrane base beta-2 Adrenergic Receptors clinical application clinical practice epithelial Na+ channel gene interaction gene therapy genetic information improved innovation response treatment response

项目摘要

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（由申请方提供）：失代偿性心力衰竭挑战肺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发生肺水肿，这表明该人群对肺水肿的易感性存在遗传影响。在肺中，肺泡Na+和液体清除主要由上皮Na+通道（ENaC）的活性调节。ENaCs的活性和数量受β 2肾上腺素能受体（ADRB 2s）调节。内源性（肾上腺素）或外源性激动剂刺激ADRB 2可增加肺泡液体清除率。因此，有三种关键蛋白质参与肺泡液体清除：ADRB 2s、ENaCs和肾上腺素。在编码ADRB 2（ENaC的α亚基）和苯乙醇胺N-甲基转移酶（PNMT，其将去甲肾上腺素转化为肾上腺素）的基因中存在常见的功能变体。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。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，特别是在肾上腺素能驱动升高的心力衰竭患者中。我们的中心假设是ADRB 2、ENaC和PNMT的遗传变异将影响基线肺液和肺液清除率对β激动剂的反应。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性化以及利用替代疗法来降低心力衰竭中肺水肿的易感性。这一建议是重要的，因为我们将探索刺激β 2-肾上腺素能受体对肺液体平衡的治疗效果，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HF患者肺水肿风险的特定疗法的理解。这项研究是创新的，因为我们将测试ADRB 2，ENaC和PNMT的遗传变异的影响。（尚未在HF患者中一起探索）对HF中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以影响HF患者的肺液体平衡，最后，我们最近开发了一种新技术来评估肺离子和液体变化，我们将结合现有的方法来扩展可用于评估肺水变化的技术。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis.

与沙丁胺醇相比，运动强度对囊性纤维化患者的影响。

DOI：
10.1016/j.rmed.2014.12.002
发表时间：
2015
期刊：
Respiratory medicine
影响因子：
4.3
作者：
Wheatley,CourtneyM;Baker,SarahE;Morgan,MaryA;Martinez,MarinaG;Morgan,WayneJ;Wong,EricC;Karpen,StephenR;Snyder,EricM
通讯作者：
Snyder,EricM

Clinical Classification of Heart Failure Patients Using Cardiac Function during Exercise.

使用运动期间心脏功能对心力衰竭患者进行临床分类。