THE ROLE OF CARDIOMYOCYTE AND CARDIOFIBROBLAST SENESCENCE IN THE AGING HEART

心肌细胞和心成纤维细胞衰老在心脏衰老中的作用

• 批准号: 8138558
• 负责人: Leroy Leon Cooper
• 金额: $ 4.18万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138558
• 关键词: 17 year old; 4 year old; Abnormal Cell; Accidents; Accounting; Acquired Immunodeficiency Syndrome; Action Potentials; Address; Adolescent; Adult; Age; Aging; Area; Arrhythmia; Biochemical; Biological Markers; Biological Models; Calcium; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cause of Death; Cell Aging; Cell Size; Cells; Cessation of life; Colorectal Cancer; DNA Damage; Data; Female; Fiber; Fibrosis; Fire - disasters; Firearms; Flow Cytometry; Functional disorder; Gene Expression; Heart; Heart Diseases; Heart failure; Housing; Immunofluorescence Immunologic; In Vitro; Incidence; Investigation; Lead; Left Ventricular Function; Life Expectancy; Link; Malignant - descriptor; Malignant neoplasm of prostate; Maps; Modeling; Molecular; Muscle Cells; Myocardium; New Zealand; Older Population; Optics; Oryctolagus cuniculus; Paraffin Embedding; Pattern; Population; Quality of life; Risk; Role; Series; Sudden Death; System; Techniques; Therapeutic; Tissues; Trichrome stain; United States; Ventricular Fibrillation; age group; age related; aged; base; cohort; emerging adult; hemodynamics; in vivo; killings; malignant breast neoplasm; mortality; novel; research study; response; senescence; sudden cardiac death

DESCRIPTION (provided by applicant): Accounting for approximately 50% of deaths related to heart disease, sudden cardiac death (SCD) is a leading cause of death in the United States; thus, understanding the mechanisms that underlie deadly arrhythmias that cause SCD could lead to preventative pharmacological and therapeutic strategies that would increase life expectancy and quality of life among a growing susceptible population. It is known that aging is associated with an increase of the incidence of SCD. Yet, much remains unknown about the mechanisms that underlie the age- related, proarrhythmic changes in the mammalian heart at the cellular and molecular level and how they are related to arrhythmogenesis and increased incidence of SCD. Thus far, we have conducted preliminary in vivo EP studies and optical mapping experiments that reveal an aging- related slowing of conduction through the His-Purkinje system and the ventricles. We have also shown an age-related increase in ventricular fibrillation inducibility, and I have performed Gomori trichrome staining on paraffin embedded sections, which revealed increased fibrosis in old hearts at the subepicardial region and between the fibers of the heart in the same area that showed slow conduction. Based on our preliminary data, I hypothesize that aging is not only associated with overall reduced cardiac function but also with the accumulation of senescent- like cardiomyocytes (CMs) and senescent cardiofibroblasts (CFs) in the cardiac muscle. Moreover, I postulate that the progressive senescence of CMs and CFs is associated with alterations in gene expression that will directly lead to abnormal myocyte contractility and abnormal cell excitation, as well as accelerated fibrosis. These alterations would lead to impaired cardiac contractility, a slowing of the conduction velocity, and a decrease in the threshold for induction of ventricular fibrillation. To that end, I am pursuing a multi-leveled approach to identify novel mechanisms that underlie malignant arrhythmias in the aging heart using comparisons between young and old rabbit cohorts, as well as comparisons among non- senescent, chronologically aged, and senescent cardiac cell populations. With a combination of in vivo and in vitro techniques (including invasive hemodynamics, immuoblotting/qPCR, immunofluorescence, flow cytometry, and single-cell calcium recordings), I hope to provide both biochemical and functional evidence revealing that cellular senescence underlies electrical and structural triggers and substrates for arrhythmias in the aging heart.

描述（由申请人提供）：占与心脏病有关的死亡的约50％，心脏病死亡（SCD）是美国的主要死亡原因；因此，了解导致SCD的致命心律不齐的基础的机制可能导致预防性的药理和治疗策略，从而增加易感人群的预期寿命和生活质量。众所周知，衰老与SCD发生率的增加有关。然而，对于哺乳动物和分子水平上哺乳动物心脏的年龄相关的，与女性心脏相关的机制以及它们与心律失常发生和SCD的发生率的增加，尚不清楚。到目前为止，我们已经进行了体内EP研究和光学映射实验的初步，这些实验揭示了通过His-Purkinje系统和心室的传导减慢衰老的减慢。我们还显示了与年龄相关的心室纤颤诱导性的增加，并且我在石蜡嵌入的切片上进行了Gomori毛状体染色，这表明在心膜下区域以及在同一区域的心脏纤维之间的旧心脏纤维化增加，显示出缓慢的传导。根据我们的初步数据，我假设衰老不仅与心脏衰老（CMS）（CMS）（CMS）和衰老心肌细胞（CFS）（CFS）（CFS）的累积相关。此外，我假设CMS和CFS的进行性衰老与基因表达的改变有关，这将直接导致异常的心肌细胞收缩力和异常细胞兴奋以及加速的纤维化。这些改变将导致心脏收缩性受损，传导速度的放缓以及诱导心室纤颤的阈值降低。为此，我正在采用一种多级方法来识别新型机制，这些机制是使用年轻人和老年兔子队之间的比较衰老心脏中的恶性心律失常，以及非衰老，年代年龄衰老和衰老心脏细胞细胞种群的比较。我希望结合体内和体外技术（包括侵入性血液动力学，不含毒性/QPCR，免疫荧光，流式细胞仪和单细胞钙记录），我希望能够提供生化和功能的证据，这些证据既可以提供电气和结构型心脏和型号的心脏和型号，以示出射击的心脏。