CYTOKINE EXPRESSION IN HUMAN & EXPERIMENTAL HEART FAILUR

人体细胞因子表达

• 批准号: 6256471
• 负责人: CARLIN S LONG
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-04 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6256471
• 关键词: ACE inhibitors; beta antiadrenergic agent; biomarker; congestive heart failure; cytokine receptors; echocardiography; gene expression; heart function; heart transplantation; heart ventricle; hemodynamics; human tissue; interleukin 1; laboratory mouse; laboratory rat; myocardium; pathologic process; phenotype; protein structure function; tissue /cell culture

Although the last ten years have seen dramatic improvements in the therapeutic approach to CHF, the expanding number of those afflicted with this disease and its persistent poor prognosis make it clear that additional novel approaches are necessary. In this regard, there has recently been an increasing appreciation of an important inflammatory component in both the development and progression of the failing heart. Specifically, increased levels of several pro-inflammatory cytokines have been found to be elevated in patients with advanced stage disease and appears to correlate with a worse prognosis. The investigations proposed in this proposal are unique and timely in two major areas: First, with the efforts of our collaborators at The University of Colorado and Temple University, these investigations will address the hypothesis that local intra-cardiac production of interleukin-1 plays a substantive role in the progression to decompensated congestive heart failure in the human heart. This will be assessed under circumstances of both established heart failure and the regression following left ventricular unloading by way of LVAD support. Second, using the well established experimental model of post-infarction cardiac failure they ask whether altering the expression/effect of such cytokines will change the transcriptional program of myocardial cells in a way associated with improved function and/or a more favorable and adaptive, remodeling process after injury. The overall hypothesis of this project is that the intra-cardiac expression of the pro-inflammatory cytokine IL-1beta is both a marker of, and progression factor for, the transition to decompensated congestive heart failure. Based on this idea, our secondary hypothesis is that interventions blocking the expression and/or effects of this cytokine will be associated with improved myocardial function and subsequently prognosis. The methods to be employed include the analysis of cytokine expression and down-stream transcriptional regulators from human samples either at the time of primary cardiac transplantation or at the time of LVAD placement and secondary transplantation. Similarly, analysis of these genes will be done in an established model of experimental heart failure in an attempt to: (1) correlate gene expression with hemodynamic severity of cardiac failure and (2) determine if targeting the expression and/or effect of IL-1 in the post-infarct heart is associated with more functional alterations in gene expression and function.

尽管在过去十年中，慢性心力衰竭的治疗方法取得了显着的进步，但患有这种疾病的人数不断增加，而且其持续的不良预后表明，需要更多的新方法。 在这方面，最近人们越来越认识到在心力衰竭的发生和进展中重要的炎症成分。 具体而言，已发现晚期疾病患者的几种促炎细胞因子水平升高，并且似乎与较差的预后相关。本提案中提出的研究在两个主要领域是独特且及时的：首先，在我们科罗拉多大学和坦普尔大学的合作者的努力下，这些研究将解决这样的假设：局部心脏内白细胞介素 1 的产生发挥着重要作用。在人类心脏失代偿性充血性心力衰竭的进展中发挥着实质性作用。 这将在已确定的心力衰竭和通过 LVAD 支持左心室卸载后消退的情况下进行评估。 其次，使用完善的梗塞后心力衰竭实验模型，他们询问改变此类细胞因子的表达/作用是否会以与功能改善和/或更有利和适应性重塑相关的方式改变心肌细胞的转录程序。受伤后的过程。该项目的总体假设是，促炎细胞因子 IL-1β 的心脏内表达既是向失代偿性充血性心力衰竭转变的标志物，也是其进展因素。 基于这个想法，我们的第二个假设是，阻断这种细胞因子的表达和/或作用的干预措施将与改善心肌功能和随后的预后相关。所采用的方法包括在初次心脏移植时或在 LVAD 放置和二次移植时对人类样本中的细胞因子表达和下游转录调节因子进行分析。类似地，将在已建立的实验性心力衰竭模型中对这些基因进行分析，试图：（1）将基因表达与心力衰竭的血流动力学严重程度相关联，以及（2）确定是否靶向IL-1的表达和/或作用。梗死后心脏中的 1 与基因表达和功能的更多功能改变相关。