Role of IGFBP3 in Neonatal Heart Regeneration

IGFBP3 在新生儿心脏再生中的作用

• 批准号: 10554959
• 负责人: Shah Rukh Ali
• 金额: $ 13.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554959
• 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.

项目摘要/摘要 这是对Shah Ali博士的K08奖的申请，他是该大学的心脏病学讲师 ，以表彰他从BASIC专业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的医学和加州大学休斯顿分校的心脏病学研究员培训。 这项提案中的研究将在领先专家赫沙姆·萨德克博士的实验室进行。 在心脏再生领域，他是一位有丰富培训经验的理想导师。此外，一个 包括著名心脏发育生物学专家埃里克·奥尔森博士在内的咨询委员会将 以书面形式提供两年一次的数据、假设和拟议实验的建设性批评，如 以及职业指导和发展。 本文描述的方案将研究新生儿心脏再生的分子机制。 目的是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，哺乳动物的心脏是一个基本静止的器官，它的初级实质细胞-- 萨德克博士实验室最近进行的开创性研究表明，成年人的心肌细胞周期受阻。 表现出新生小鼠心脏完全再生的现象。脑室切除后 心尖或手术诱导的心肌梗死(MI)，小于一周龄的小鼠表现为完全性心肌梗死 心肌细胞更新，这与成年小鼠由于未能实现 有意义的心肌生成。一种命运映射方法表明，现有的心肌细胞分裂生成 新生儿损伤后新的心肌细胞。 根据上述发现，我们推测幼鼠体内存在心脏变力因子。 导致新生儿心肌梗死后心肌细胞旺盛增殖的心脏。我们的初步数据确定了胰岛素- 与生长因子结合蛋白IGFBP3一样，作为一种心肌细胞有丝分裂原，可以使心肌细胞分裂。 耐人寻味的是，在没有损伤的情况下或在发育过程中，心脏不表达这种因子，这表明 它是特定的损伤诱导的信号通路的一部分。具体目标提出：1)确定和 确定在损伤时分泌IGFBP3的细胞的特征，2)确定IGFBP3是否对 成人心肌梗死后新生儿再生和/或足以促进心肌细胞更新，以及3)确定 IGFBP3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 作为一名内科医生、科学家和心脏病专家。作为一名独立的私人侦探，阿里博士将研究调解 新生儿心脏再生为成人心脏病新疗法的开发提供信息，合乎逻辑 延长他的K08提案。