Periostin in Myocardial Injury and Regeneration

描述（由申请人提供）： 一个为期5年的研究计划，提出了加强在儿科心脏病学的学术生涯。主要研究者已完成儿科住院医师培训和儿科心脏病学研究金。这个职业发展计划将增加他在心肌再生和心力衰竭领域的科学技能的深度。两位国际知名的教师，大卫克拉彭和马克基廷，将赞助申请人。一个由各自领域的三位顶尖科学家组成的咨询委员会将为申请人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瘢痕形成，而不是增殖，增殖是再生的细胞基础。这种再生能力的丧失是心血管疾病发病率和死亡率的重要原因。相比之下，低等脊椎动物，例如蝾螈和斑马鱼，可以通过心肌细胞增殖再生心脏。成年哺乳动物心肌细胞被认为是静止的，即它们不增殖。然而，基廷实验室最近的工作表明，哺乳动物的心肌细胞保留了潜在的增殖潜力。主要研究者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，骨膜蛋白，细胞外基质的成分，刺激心肌细胞增殖。骨膜蛋白在正常心肌中不存在，但在损伤的心脏中表达。我们的数据支持骨膜蛋白在心肌恢复中具有有益功能的假设。具体目标是：1.描述骨膜蛋白在体外的细胞效应：我们将研究骨膜蛋白对培养的原代大鼠心肌细胞中心肌细胞周期进程、增殖和存活的影响。2.在体外表征骨膜蛋白的分子功能：我们将表征心肌细胞中骨膜蛋白激活的受体和细胞内信号通路。3.骨膜蛋白在体内心脏中的功能表征：我们将使用腺病毒基因转移在正常大鼠心脏中表达骨膜蛋白。我们还将在心肌损伤的大鼠中破坏骨膜蛋白的作用。我们将通过超声心动图和导管插入术评估心脏功能，并通过免疫荧光显微镜确定组织反应。这些研究将提供第一个详细的功能分析骨膜蛋白在受损的哺乳动物心肌的恢复。长期目标是为心力衰竭提供新的治疗方法。 (End摘要）

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)