Initiation of Cardiac Hypertrophy

心脏肥大的开始

• 批准号: 7254909
• 负责人: Subha Sen
• 金额: $ 36.27万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254909
• 关键词: Age; Apoptosis; Atrial Natriuretic Factor; Cardiac; Cardiac Myocytes; Cause of Death; Cell division; Chronic; Chronic Phase; Connexins; DNA Microarray Chip; DNA Microarray format; Data; Disease; Disease Progression; Drug usage; Echocardiography; Electron Microscope; FOS gene; Failure; Funding; Gene Chips; Gene Expression; Genes; Genetic Transcription; Growth; Growth Factor; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; High Blood Pressure; Human; Hypertension; Hypertrophy; Inbred SHR Rats; Individual; Intervention; Investigation; Laboratories; Measures; Mechanics; Modeling; Molecular; Molecular Profiling; Mus; Muscle Cells; Myocardial; Myocardium; Myosin Heavy Chains; Pathogenesis; Pathway interactions; Pharmacological Treatment; Phase; Play; Process; Protein Biosynthesis; Protein Overexpression; Proteins; Purpose; RNA Interference; Research Personnel; Role; Small Interfering RNA; Staging; Stress; System; TP53 gene; Techniques; Technology; Testing; Tetanus Helper Peptide; Tetracycline; Tetracyclines; Therapeutic; Time; Transactivation; Transgenic Organisms; Transmission Electron Microscopy; United States; Up-Regulation; Ursidae Family; Week; Work; base; c-myc Proto-Oncogenes; cell growth; cytokine; design; interdisciplinary approach; mouse model; multidisciplinary; myotrophin; novel; prevent; programs; release factor; transmission process

DESCRIPTION (provided by applicant): Cardiac hypertrophy and heart failure are leading causes of death in the United States. However, the molecular processes underlying the pathogenesis of heart disease have not been thoroughly understood. During investigations spanning several years we identified and profiled in spontaneously hypertensive rats a 12-kDa protein, myotrophin (Myo), that stimulates myocyte growth. The past funding period has yielded these novel observations: (1) Myo overexpression causes cardiac hypertrophy that devolves to heart failure, and the molecular profiles of associated cytokines/growth factors differ in early- vs. late-stage disease; (2) activation of the NFkappaB pathway is necessary for the progression of Myo-induced cardiac hypertrophy; (3) at the point when chronic hypertrophy becomes heart failure, cell division and apoptosis of cardiac myocytes occur in parallel; and (4) Myo overexpression elicits significant, robust overexpression of p53, highlighting a possible role of p53 in this process. Each finding would provide fertile ground for more investigation, but we chose in this renewal proposal to focus on the effects of turning Myo gene expression on and off and defining the role of p53 in the hypertrophic process. We hypothesize that Myo acts directly on myocyte during initiation of cardiac hypertrophy, whereas it acts in synergy with p53 and other cytokines/growth factors at the point of transition to heart failure. To test this hypothesis, we propose a multidisciplinary approach to evaluating the effects of the expression or nonexpression of the Myo gene by (a) using a let-control switch; (b) silencing the Myo gene using siRNA technology; or (c) administering pharmacological treatment conventionally given to humans with heart failure. Our specific aims are (1) to study the effects of altering Myo gene expression by either (a) using a tetracycline transactivation system or (b) silencing the Myo gene using siRNA; (2) to study the effects of individual pharmacologic agents, alone or in combination, on the degree of hypertrophy as it progresses to heart failure, associated with molecular changes; (3) to define what relationship p53 has to Myo in hypertrophy and when it worsens to failure; (4) to evaluate structural changes observed during initiation/progression of hypertrophy to heart failure by transmission electron microscopy and (5) to determine cardiac function by echocardiogram to correlate observed morphological and molecular changes. These findings bear crucially upon the treatment of heart disease in humans. Together with investigations into additional molecular mechanisms that underlie the progression of cardiac hypertrophy to heart failure, the findings will facilitate more effective intervention, not only in decisions regarding the timing of intervention, but also in the design of appropriate molecularly based therapies.

描述（由申请人提供）：心脏肥大和心力衰竭是美国的主要死亡原因。然而，心脏病发病机制的分子过程尚未完全了解。在几年的研究中，我们在自发性高血压大鼠中发现并分析了一种12 kDa的蛋白质，肌营养素（Myo），它刺激肌细胞生长。过去的资助期已经产生了这些新的观察结果：（1）Myo过表达导致心肌肥大，进而发展为心力衰竭，并且相关细胞因子/生长因子的分子谱在早期与晚期疾病中不同;（2）NF κ B通路的激活对于Myo诱导的心肌肥大的进展是必要的;（3）在慢性肥厚变成心力衰竭时，心肌细胞的细胞分裂和凋亡平行发生;（4）Myo过表达引起p53显著、强烈的过表达，突出了p53在该过程中的可能作用。每一项发现都将为更多的研究提供肥沃的土壤，但我们选择在这个更新的建议，把重点放在打开和关闭Myo基因表达的影响，并定义p53在肥大过程中的作用。我们假设Myo在心肌肥厚的起始过程中直接作用于心肌细胞，而在向心力衰竭转变时与p53和其他细胞因子/生长因子协同作用。为了验证这一假设，我们提出了一个多学科的方法来评估Myo基因的表达或不表达的影响，通过（a）使用一个let控制开关;（B）沉默Myo基因使用siRNA技术;或（c）管理常规给予人类心力衰竭的药物治疗。我们的具体目标是（1）研究通过（a）使用四环素反式激活系统或（B）使用siRNA沉默Myo基因来改变Myo基因表达的作用;（2）研究单独或组合的单个药理学试剂对随着其进展为心力衰竭的肥大程度的作用，与分子变化相关;（3）确定p53与心肌肥厚及心肌肥厚与心力衰竭的关系;（4）通过透射电镜评价心肌肥厚开始/进展至心力衰竭过程中观察到的结构变化;（5）通过超声心动图确定心脏功能，以将观察到的形态学和分子变化联系起来。这些发现对人类心脏病的治疗至关重要。再加上对心脏肥大进展为心力衰竭的其他分子机制的研究，这些发现将有助于更有效的干预，不仅在干预时机的决定方面，而且在设计适当的分子治疗方面。