Maladaptive Remodeling in Aging Myocardium

衰老心肌的适应不良重塑

• 批准号: 7682021
• 负责人: FRANCIS G SPINALE
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682021
• 关键词: Affect; Aging; Automobile Driving; Binding; Binding Proteins; Blood; Cardiac; Cardiac Myocytes; Cause of Death; Cicatrix; Complex; Development; Diagnostic; Elderly; Enzymes; Event; Extracellular Matrix; Family; Fibroblasts; Fibrosis; Functional disorder; Genetic Transcription; Growth; Growth Factor; Heart; Heart failure; Hospitalization; Hypertension; Hypertrophy; Incidence; Integral Membrane Protein; Laboratories; Left ventricular structure; Link; Matrix Metalloproteinases; Measures; Medical; Messenger RNA; Metabolism; Metalloproteinase Gene; Methods; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myocardial; Myocardium; Pathway interactions; Patients; Peptide Hydrolases; Performance; Prevention; Process; Proteins; Regulation; Reporter; Research; Research Project Grants; Risk; Secondary to; Series; Signal Transduction; Signaling Molecule; Staging; Stimulus; Structure; System; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Organisms; aging population; cardiogenesis; care delivery; constriction; cytokine; disability; human MMP14 protein; hypertension treatment; improved; insight; mortality; novel; older patient; overexpression; patient population; pressure; promoter; public health relevance

DESCRIPTION (provided by applicant): A common cause for the development and progression of HF in the elderly is hypertension, which causes a pressure overload resulting in hypertrophy (LVH). While LVH is a complex multifactorial process which involves changes in myocardial growth and metabolism, a common structural event is increased extracellular matrix (ECM) accumulation (ie fibrosis). One of the important observations from this past research period was that a unique MMP type, the membrane type-1 MMP (MT1-MMP) was associated with significant ECM accumulation, particularly within the aging myocardium. One potent profibrotic pathway is transforming growth factor (TGF) which is held in an inactive form by the latency-associated TGF binding protein-1 LTBP-1. Our preliminary studies demonstrate that MT1-MMP processes LTBP-1, which would yield an active form of TGF. Thus, the central hypothesis of this continuing research project is that increased induction and expression of MT1-MMP causes an amplified profibrotic cascade which is a molecular cornerstone of ECM accumulation with LVH; particularly within the aging myocardium. This project will perform a step-wise set of studies that will use novel transgenic constructs which will allow for the quantitation of MT1-MMP promoter activity, proteolytic activity, LTBP-1 processing, and most importantly regulate MT1-MMP expression during the progression of LVH and with aging. Moreover, this study will demonstrate that regional regulation of MT1-MMP induction and activity directly changes the course of myocardial fibrosis that occurs within the aging myocardium; particularly with the superimposition of LVH. The results from these proposed studies will identify a novel proteolytic pathway which regulates ECM accumulation in the context of developing LVH, and thereby provide new critical insights into how ECM accumulation- ie fibrosis can occur within the aging myocardium, in particular with a pressure overload stimulus. These studies will identify a novel proteolytic pathway which contributes to ECM accumulation within the aging myocardium and the development of LVH; thereby defining molecular targets for improved diagnostic and therapeutic strategies for elderly patients at risk for LVH induced HF. PUBLIC HEALTH RELEVANCE: One of the leading causes of death and disability in the VA patient population is the development and progression of heart failure. A common underlying cause of heart failure is from long standing high blood pressure which will result in the heart muscle becoming thickened with an increase in scar- like tissue- which is called fibrosis. Heart fibrosis will result in the inability of the heart to accept blood and as a result, these patients will be severely weakened, and often require hospitalization. As a consequence of the aging population, the incidence of heart failure is predicted to increase at an alarming rate resulting in a significant strain on medical care delivery systems; in particular the VA. One major hurdle that must be overcome to improve treatment and prevention of this form of heart failure, is to identify the pathways which cause heart fibrosis. This study will identify a novel protein that is likely to be central in the early development of heart fibrosis, secondary to hypertension and heart failure. These studies will set the stage for developing novel methods to identify patients at risk for developing this form of heart failure as well as targets for interrupting the inexorable progression to heart failure in the vulnerable VA patient population.

描述（由申请人提供）： 老年人心力衰竭发生和进展的一个常见原因是高血压，它会导致压力超负荷，导致肥厚 (LVH)。虽然 LVH 是一个复杂的多因素过程，涉及心肌生长和代谢的变化，但常见的结构事件是细胞外基质 (ECM) 积累增加（即纤维化）。过去研究阶段的重要观察结果之一是，一种独特的 MMP 类型，即膜 1 型 MMP (MT1-MMP)，与显着的 ECM 积累相关，特别是在老化的心肌内。一种有效的促纤维化途径是转化生长因子 (TGF)，它通过潜伏相关 TGF 结合蛋白 1 LTBP-1 保持非活性形式。我们的初步研究表明 MT1-MMP 处理 LTBP-1，从而产生活性形式的 TGF。因此，这个持续研究项目的中心假设是，MT1-MMP 的诱导和表达增加会导致促纤维化级联放大，这是 ECM 积累与 LVH 的分子基石；尤其是在老化的心肌内。该项目将进行一系列分步研究，将使用新型转基因构建体，对 MT1-MMP 启动子活性、蛋白水解活性、LTBP-1 加工进行定量，最重要的是在进展过程中调节 MT1-MMP 表达。 LVH 与衰老有关。此外，这项研究将证明MT1-MMP诱导和活性的区域调节直接改变老化心肌内发生的心肌纤维化进程；尤其是 LVH 的叠加。这些拟议研究的结果将确定一种新的蛋白水解途径，该途径在发生 LVH 的情况下调节 ECM 积累，从而为 ECM 积累（即衰老心肌内纤维化）如何发生提供新的重要见解，特别是在压力超负荷刺激下。这些研究将确定一种新的蛋白水解途径，该途径有助于老化心肌内 ECM 的积累和 LVH 的发展；从而确定分子靶标，以改善有 LVH 诱发心力衰竭风险的老年患者的诊断和治疗策略。 公共卫生相关性： 退伍军人管理局患者群体死亡和残疾的主要原因之一是心力衰竭的发生和进展。心力衰竭的一个常见根本原因是长期高血压，这会导致心肌变厚，疤痕样组织增加，称为纤维化。心脏纤维化会导致心脏无法接受血液，因此这些患者的身体会严重虚弱，通常需要住院治疗。由于人口老龄化，心力衰竭的发病率预计将以惊人的速度增加，从而给医疗保健提供系统带来巨大压力；特别是弗吉尼亚州。为了改善这种形式的心力衰竭的治疗和预防，必须克服的一个主要障碍是确定导致心脏纤维化的途径。这项研究将鉴定出一种新的蛋白质，它可能在继发于高血压和心力衰竭的心脏纤维化的早期发展中起重要作用。这些研究将为开发新方法奠定基础，以识别有患这种形式心力衰竭风险的患者，并确定阻止脆弱 VA 患者群体不可避免地发展为心力衰竭的目标。