Role of IGFBP3 in Neonatal Heart Regeneration

项目总结/摘要 这是一份K 08奖的申请，申请人是医学博士Shah Ali，他是该大学的心脏病学讲师。 得克萨斯州西南部（UTSW），为他从教师到独立调查员的过渡，在基础 心血管生物学，重点是心脏再生。他已完成内部住院医师培训， 医学在加州圣弗朗西斯科大学和奖学金培训心脏病学在UTSW。 该提案中的研究将在领先专家Hesham Sadek博士的实验室进行 他是心脏再生领域的专家，也是一位具有丰富培训经验的理想导师。此外， 包括心脏发育生物学著名专家埃里克·奥尔森博士在内的咨询委员会将 以书面形式对数据、假设和拟议的实验提出两年一次的建设性批评， 以及职业指导和发展。 本文所述的建议将探讨新生儿心脏再生的分子机制 研究人员在小鼠身上进行了一项研究，旨在将这些发现转化为人类，以产生治疗心脏病的新疗法。 虽然哺乳动物的心脏是一个主要静止的器官，其主要的实质细胞-- 心肌细胞-是细胞周期停滞在成人，最近的开创性研究，从博士的实验室萨德克有 其特征在于新生小鼠中完全心脏再生的现象。切除脑室后 在心尖或心脏诱导的心肌梗死（MI）中，小于一周龄的小鼠表现出完全的 这与成年小鼠形成鲜明对比，成年小鼠由于未能实现心肌细胞更新而形成纤维化疤痕。 有意义的心肌形成一种命运绘图方法表明，现有的心肌细胞分裂产生 新生儿损伤后的新心肌细胞。 基于上述发现，我们推测幼鼠体内存在着强心因子 心脏，引发新生儿心肌梗死后心肌细胞增殖。我们的初步数据表明胰岛素- 如生长因子结合蛋白IGFBP 3，作为心肌细胞分裂原，使心肌细胞分裂。 有趣的是，在没有损伤或发育过程中，该因子在心脏中不表达，这表明 它是特定损伤诱导信号通路的一部分。具体目标是：（1）确定和 表征响应于损伤而分泌IGFBP 3的细胞，2）确定IGFBP 3是否是 新生儿再生和/或足以促进成人MI后的心肌细胞更新，以及3）确定 IGFBP 3是否利用IGF信号刺激心肌细胞分裂。 最终，这里概述的培训和研究计划将支持阿里博士实现独立 作为一个医生科学家心脏病专家作为一名独立的PI，阿里博士将研究介导 新生儿心脏再生告知成人心脏病的新疗法的发展，一个合乎逻辑的 K 08提案的延期。

Project Summary/Abstract This is an application for a K08 award for Dr. Shah Ali, MD, an Instructor in Cardiology at the University of Texas Southwestern (UTSW), for his transition from Instructor to independent investigator in basic cardiovascular biology with a focus on cardiac regeneration. He has completed residency training in Internal Medicine at the University of California San Francisco and fellowship training in Cardiology at UTSW. The research in this proposal will be conducted in the laboratory of Dr. Hesham Sadek, a leading expert in the field of cardiac regeneration and an ideal mentor with significant training experience. In addition, an Advisory Committee that includes Dr. Eric Olson, a renowned expert in cardiac developmental biology, will provide biannual constructive criticism of data, hypotheses, and proposed experiments in a written manner as well as career guidance and development. The proposal described herein will investigate the molecular mechanisms of neonatal heart regeneration in mice with an aim at translating these findings to humans to generate novel therapies to treat heart diseases. Although the mammalian heart is known to be a mostly quiescent organ whose primary parenchymal cell – the cardiomyocyte – is cell cycle-arrested in adults, recent pioneering studies from the laboratory of Dr. Sadek have characterized a phenomenon of complete cardiac regeneration in neonatal mice. After resection of the ventricular apex or surgically-induced myocardial infarction (MI), mice younger than one week of age exhibit complete cardiomyocyte renewal, in stark contrast to adult mice that develop a fibrotic scar due to failure to achieve meaningful cardiomyogenesis. A fate-mapping approach showed that existing cardiomyocytes divide to generate new cardiomyocytes after neonatal injuries. Based on the above findings, we hypothesized that there are cardiotropic factors within the young mouse heart that elicit the robust cardiomyocyte proliferation after neonatal MI. Our preliminary data identifies insulin- like growth factor binding protein, IGFBP3, as a cardiomyocyte mitogen that enables cardiomyocyte division. Intriguingly, this factor is not expressed in the heart in the absence of injury or during development, suggesting that it is part of a specific injury-induced signaling pathway. The specific aims propose to: 1) identify and characterize the cell that secretes IGFBP3 in response to injury, 2) determine whether IGFBP3 is necessary for neonatal regeneration and/or sufficient to promote cardiomyocyte renewal after adult MI, and 3) determine whether IGFBP3 utilizes IGF signaling to stimulate cardiomyocyte division. Ultimately, the training and research plan outlined here will support Dr. Ali as he achieves independence as a physician-scientist-cardiologist. As an independent PI, Dr. Ali will study the mechanisms that mediate neonatal heart regeneration to inform the development of novel therapeutics for adult heart disease, a logical extension of his K08 proposal.