Role of IGFBP3 in Neonatal Heart Regeneration

IGFBP3 在新生儿心脏再生中的作用

• 批准号: 10215156
• 负责人: Shah Rukh Ali
• 金额: $ 13.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215156
• 关键词: Address; Adult; Advisory Committees; Age; Award; Beta Cell; Binding; Biology; Blood Vessels; California; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Count; Cell Cycle Arrest; Cell Death; Cell Lineage; Cell Transplantation; Cell division; Cells; Cessation of life; Cicatrix; Data; Development; Developmental Biology; Endothelial Cells; Endothelium; Excision; Exhibits; Failure; Fellowship; Fibroblasts; Genetic Models; Healthcare Systems; Heart; Heart Diseases; Heart Transplantation; Heart failure; Human; IGF2 gene; Impairment; Injury; Insulin Receptor; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth-Factor-Binding Proteins; Internal Medicine; Knockout Mice; Knowledge; Laboratories; Laboratory Study; Life; Mechanics; Mediating; Mentors; Mitogens; Mitosis; Molecular; Mus; Muscle Cells; Myocardial Infarction; Natural regeneration; Neonatal; Operative Surgical Procedures; Organ; Output; Patients; Pharmaceutical Preparations; Physicians; Protein Family; Proteins; Recombinant Insulin-Like Growth Factor; Recombinants; Research; Research Personnel; Residencies; Role; San Francisco; Scientist; Serum; Signal Pathway; Signal Transduction; Source; Texas; Tissues; Training; Translating; Universities; Ventricular; Vocational Guidance; base; cardiac regeneration; career development; cell type; conditional knockout; defined contribution; experience; experimental study; heart function; insight; instructor; ischemic cardiomyopathy; mouse model; mutant; neonatal injury; neonatal mice; neonate; novel; novel therapeutics; overexpression; paracrine; regenerative; regenerative therapy; response to injury; therapeutic candidate

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.

项目概要/摘要 这是大学心脏病学讲师 Shah Ali 医学博士的 K08 奖项申请 德克萨斯西南大学 (UTSW) 的教授，表彰他从基础学科的讲师转变为独立调查员 心血管生物学，重点是心脏再生，他已完成内科住院医师培训。 加州大学旧金山分校医学专业和 UTSW 心脏病学专科培训。 本提案中的研究将在领先专家 Hesham Sadek 博士的实验室进行 在心脏再生领域，是一位具有丰富培训经验的理想导师。 包括心脏发育生物学著名专家 Eric Olson 博士在内的咨询委员会将 以书面方式每半年对数据、假设和提议的实验提出建设性批评： 以及职业指导和发展。 本文描述的提案将研究新生儿心脏再生的分子机制 在小鼠身上进行实验，旨在将这些发现转化为人类，以产生治疗心脏病的新疗法。 尽管众所周知，哺乳动物心脏是一个大部分静止的器官，其初级实质细胞 - 心肌细胞 – 在成人中是细胞周期停滞的，Sadek 博士实验室最近的开创性研究表明 描述了新生小鼠心室切除后心脏完全再生的现象。 心尖部或手术诱发的心肌梗死 (MI)，不到一周龄的小鼠表现出完全 心肌细胞更新，与成年小鼠形成鲜明对比，成年小鼠因未能实现心肌细胞更新而形成纤维化疤痕 有意义的心肌发生方法表明现有的心肌细胞分裂产生。 新生儿损伤后新生的心肌细胞。 根据上述发现，我们发现幼鼠体内存在促心因子 我们的初步数据表明，胰岛素可以在新生儿心肌梗死后引发强劲的心肌细胞增殖。 像生长因子结合蛋白 IGFBP3 一样，作为心肌细胞有丝分裂原，使心肌细胞分裂。 有趣的是，在没有损伤或发育过程中，该因子不会在心脏中表达，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) 识别和确定。 表征响应损伤而分泌 IGFBP3 的细胞，2) 确定 IGFBP3 是否是损伤所必需的 新生儿再生和/或足以促进成人 MI 后心肌细胞更新，以及 3) 确定 IGFBP3 是否利用 IGF 信号传导刺激心肌细胞分裂。 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 作为一名医生、科学家、心脏病专家，阿里博士将研究调解机制。 新生儿心脏再生为成人心脏病新疗法的开发提供信息，这是一种合乎逻辑的方法 延长他的 K08 提案。