Periostin in Myocardial Injury and Regeneration

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。校长 调查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 发展计划将增加他在心肌再生和心脏领域的科学技能 失败了。两位享誉国际的教师大卫·克拉彭和马克·基廷将赞助 申请人。一个由三位各自领域的顶尖科学家组成的咨询委员会将提供 应聘者有研究和职业建议。 人类不会再生他们的心脏。相反，人类的心脏对损伤的反应是形成疤痕，而不是 随着增殖，再生的细胞基础。这种无法再生的能力极大地促进了 心血管发病率和死亡率。相比之下，较低级的脊椎动物，如纽特和斑马鱼，可以 通过心肌细胞增殖使他们的心脏再生。成年哺乳动物心肌细胞被认为是 静止的，即它们不会扩散。然而，基廷实验室最近的研究表明 哺乳动物心肌细胞具有潜在的增殖潜能。PI的重点是识别 释放哺乳动物心肌细胞增殖潜能的因素。初步数据显示， Periostin是细胞外基质的一种成分，可以刺激心肌细胞的增殖。Periostin缺失 来自正常心肌，但在受损心脏中表达。我们的数据支持Periostin的假设 对心肌恢复有有益作用。具体目标是： 1.研究Periostin的体外细胞效应：我们将研究Periostin对细胞生长的影响 原代培养大鼠心肌细胞的细胞周期进程、增殖和存活。 2.体外鉴定Periostin的分子功能：我们将鉴定其受体和 Periostin激活的心肌细胞内信号通路。 3.研究Periostin在心脏中的功能：我们将在正常大鼠心脏中表达Periostin 使用腺病毒基因转移。我们还将用药物干扰大鼠的骨膜蛋白作用 心肌损伤。我们将通过超声心动图和导管术评估心功能，并 用免疫荧光显微镜测定组织反应。 这些研究将首次提供Periostin在伤者康复过程中的详细功能分析 哺乳动物的心肌。长期目标是为心力衰竭提供新的治疗方法。

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 PI 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.