Periostin in Myocardial Injury and Regeneration

描述(由申请人提供)： 一项为期5年的研究计划被提出，以促进儿科心脏病学的学术生涯。首席研究员已经完成了儿科住院医师资格和儿科心脏病学研究员学位。这份职业发展计划将为他在心肌再生和心力衰竭领域的科学技能增添深度。两位享誉国际的教职员工大卫·克拉彭和马克·基廷将为申请者提供赞助。一个由三位各自领域的顶尖科学家组成的咨询委员会将为申请者提供研究和职业建议。人类不会再生他们的心脏。相反，人类心脏对损伤的反应是形成疤痕，而不是增殖，增殖是再生的细胞基础。这种再生能力的丧失极大地增加了心血管疾病的发病率和死亡率。相比之下，较低级的脊椎动物，如蝾螈和斑马鱼，可以通过心肌细胞增殖来再生它们的心脏。成年哺乳动物的心肌细胞被认为是静止的，即它们不会增殖。然而，基廷实验室最近的研究表明，哺乳动物心肌细胞保持着潜在的增殖潜力。首席研究员专注于确定释放哺乳动物心肌细胞增殖潜力的因素。初步数据表明，细胞外基质的一种成分Periostin可以刺激心肌细胞增殖。Periostin在正常心肌中不表达，但在损伤心肌中表达。我们的数据支持Periostin在心肌恢复中具有有益功能的假设。1.研究Periostin的体外细胞效应：研究Periostin对原代培养的大鼠心肌细胞周期、增殖和存活的影响。2.Periostin的体外分子功能研究：我们将对Periostin在心肌细胞中的受体和激活的细胞内信号通路进行研究。3.研究Periostin在心脏中的功能：利用腺病毒基因转移技术在正常大鼠心脏中表达Periostin。我们还将从药理上干扰Periostin对心肌损伤大鼠的作用。超声心动图和心导管检查评价心功能，免疫荧光显微镜观察组织反应。这些研究将首次提供Periostin在恢复受损哺乳动物心肌中的详细功能分析。长期目标是为心力衰竭提供新的治疗方法。 (摘要结束)

DESCRIPTION (provided by applicant): A 5-year research program is proposed to enhance an academic career in Pediatric Cardiology. The principal investigator has completed a residency in Pediatrics and a fellowship in Pediatric Cardiology. This career development plan will add depth to his scientific skills in the field of myocardial regeneration and heart failure. Two internationally renowned faculty members, David Clapham and Mark Keating, will sponsor the applicant. An advisory committee consisting of three leading scientists in their fields will provide the applicant with research and career advice. Humans do not regenerate their hearts. Instead, the human heart responds to injury with scar formation, not with proliferation, the cellular basis of regeneration. This inability to regenerate contributes significantly to cardiovascular morbidity and mortality. By contrast, lower vertebrates, e.g. newt and zebrafish, can regenerate their hearts by cardiomyocyte proliferation. Adult mammalian cardiomyocytes are believed to be quiescent, i.e. they do not proliferate. However, recent work in the Keating laboratory suggests that mammalian cardiomyocytes retain the latent potential to proliferate. The Principal Investigator focused on the identification of factors that release the proliferative potential of mammalian cardiomyocytes. Preliminary data indicate that periostin, a component of the extracellular matrix, stimulates cardiomyocyte proliferation. Periostin is absent from normal myocardium, but expressed in the injured heart. Our data support the hypothesis that periostin has a beneficial function in myocardial recovery. The specific aims are: 1. Characterize the cellular effects of periostin in vitro: We will study the effect of periostin on cardiomyocyte cell cycle progression, proliferation, and survival in cultured primary rat cardiomyocytes. 2. Characterize the molecular function of periostin in vitro: We will characterize the receptor and the intracellular signaling pathways activated by periostin in cardiomyocytes. 3. Characterize the function of periostin in the heart in vivo: We will express periostin in the normal rat heart using adenoviral gene transfer. We will also pharmacologically disrupt the periostin action in rats with myocardial injury. We will evaluate the cardiac function with echocardiography and catheterization, and determine the tissue response with immunofluorescence microscopy. These studies will provide the first detailed functional analysis of periostin in the recovery of the injured mammalian myocardium. The long-term goal is to provide new therapeutic approaches to heart failure. (End of Abstract)