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Control of Cardiac Lineage Commitment and Differentiation in Murine Development

小鼠发育中心脏谱系承诺和分化的控制

基本信息

批准号：
8650301
负责人：
IBRAHIM J DOMIAN
金额：
$ 13.8万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8650301
关键词：
Adult Advisory Committees Affect American Area Biology Cardiac Cardiology Cardiovascular Diseases Cardiovascular system Clinical Color Committee Members Congenital Abnormality Defect Development Developmental Biology Diagnosis Disease Doctor of Philosophy ES Cell Line Ectoderm Embryo Embryonic Development Endoderm Equilibrium Event Family Functional RNA Future Gene Expression Gene Targeting General Hospitals Genes Genetic Markers Heart Heart Diseases Hospitalization Human In Situ Hybridization In Vitro Institutes Internal Medicine Knock-in Mouse Left ventricular structure Massachusetts Mentorship Mesoderm MicroRNAs Molecular Morbidity - disease rate Morphogenesis Mus Myocardial Pathway interactions Phenotype Physicians Physiological Physiology Play Population Program Development Proteins Regenerative Medicine Research Research Personnel Right ventricular structure Role Scientist Small RNA Stem cells System Testing Training Training Programs Transgenic Mice Transgenic Organisms United States Ventricular septum Work base career career development congenital heart disorder dosage embryonic stem cell homeodomain in vivo islet loss of function medical schools mortality progenitor programs public health relevance recombinase regenerative therapy research study stem cell biology tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a five-year training program for the development of an academic career in Cardiology. The principle investigator obtained his MD/PhD from Stanford School of Medicine and has completed clinical training in Internal Medicine, Cardiology, and Interventional Cardiology at Massachusetts General Hospital (MGH). He will now focus on the study of stem cell and developmental biology as it pertains to cardiac disease under the mentorship of Dr. Kenneth Chien. Dr. Chien, a leader in the field of cardiac development, is chief of the Cardiovascular Research Center (CVRC) at the MGH and Leader of the Cardiovascular Disease Program at the Harvard Stem Cell Institute (HSCI). He has trained numerous physician scientists. To promote training in stem cell biology, the principle investigator has already spent one year training with Dr. Stuart Orkin, a pioneer in stem cell biology. Dr. Orkin will continue to play a prominent role in training the principle investigator as an Advisory Committee member. In addition, Dr. Kenneth Bloch and Dr. Randall Peterson, both recognized leaders in cardiovascular biology, will serve mentorship roles on the Advisory Committee. The CVRC and the HSCI provide an ideal setting for training physician- scientists in the rapidly converging areas of cardiac development and stem cell biology. The research program will focus on lineage commitment and differentiation during murine cardiac development. Acquired and congenital heart disease represents a leading cause of mortality and morbidity in the world and many of the genes important in cardiac development have been implicated in human congenital heart disease. Defining the molecular pathways that control cardiac development is essential to understanding the pathophysiologic basis of these diseases and will contribute to the scientific basis of regenerative medicine. Recently, small non-coding RNA molecules called microRNAs (miRNAs) have been shown to regulate gene expression by titrating the dosage of critical proteins. Although several miRNAs are enriched in the developing heart and appear to control the balance of myocardial expansion and differentiation, the full temporal and spatial repertoire of cardiac miRNAs has yet to be established. The mammalian heart develops from two closely related sets of cardiac progenitors, first heart field (FHF) which gives rise to the left ventricle (LV) and the second heart field (SHF) which gives rise to the right ventricle (RV) and outflow tract (OFT). To investigate the role of miRNAs in controlling the development of these lineages, we have used distinct genetic markers to develop a two-color transgenic murine system. We were thereby able to purify FHF and SHF progenitors from embryos and embryonic stem cells differentiating in vitro, and to identify a set of miRNAs that are differentially expressed in the two cardiac lineages. Significantly we identify miR200a and miR200b (miR200), two closely related miRNAs transcribed in a polycistronic fashion, as the first miRNAs specific for early FHF progenitors within the developing heart and in preliminary experiments demonstrate that they appear to play a key role in the normal development of that lineage. We hypothesize that miR200 regulates cardiac development by promoting FHF progenitor expansion and differentiation and suppressing commitment to other lineages. We further hypothesize that miR200 functions by controlling specific target genes and is necessary for normal morphogenesis and function of the mature mammalian heart. To test this, we propose the following specific aims: 1) Determine if miR200 is promotes FHF development by supporting mesoderm differentiation and suppressing endoderm and ectoderm differentiation; 2) Determine the mechanisms by which miR200 controls FHF development; 3) Determine the role of miR200 during embryonic development. The tools and understanding developed here will contribute to the scientific basis of cardiac regenerative therapies. PUBLIC HEALTH RELEVANCE: Heart disease affects millions of Americans every year and is a leading cause of hospitalization in the United States. Understanding how the heart develops will help us understand how the heart becomes diseased. This study will give us clues for the future on how to diagnose and treat cardiac birth defects and adult diseases.

描述（由申请人提供）：本提案描述了一个为期五年的培训计划，用于发展心脏病学的学术生涯。主要研究者获得了斯坦福大学医学院的医学博士/博士学位，并在马萨诸塞州总医院（MGH）完成了内科、心脏病学和介入心脏病学的临床培训。他现在将专注于干细胞和发育生物学的研究，因为它涉及到心脏疾病的指导下博士。钱博士是心脏发育领域的领导者，是MGH心血管研究中心（CVRC）的负责人，也是哈佛干细胞研究所（HSCI）心血管疾病项目的负责人。他培养了许多医学科学家。为了促进干细胞生物学的培训，主要研究者已经与干细胞生物学的先驱斯图尔特·奥金博士一起接受了一年的培训。Orkin博士将继续在培训主要研究者作为咨询委员会成员方面发挥突出作用。此外，Kenneth Bloch博士和Randall Peterson博士都是心血管生物学领域公认的领导者，他们将在咨询委员会担任导师。CVRC和HSCI为培训心脏发育和干细胞生物学快速融合领域的医生-科学家提供了理想的环境。该研究计划将集中在小鼠心脏发育过程中的谱系承诺和分化。获得性和先天性心脏病代表了世界上死亡率和发病率的主要原因，并且心脏发育中重要的许多基因与人类先天性心脏病有关。确定控制心脏发育的分子通路对于理解这些疾病的病理生理基础至关重要，并将有助于再生医学的科学基础。最近，被称为microRNA（miRNAs）的小的非编码RNA分子已被证明可以通过滴定关键蛋白质的剂量来调节基因表达。虽然几种miRNAs在发育中的心脏中富集，并且似乎控制心肌扩张和分化的平衡，但心脏miRNAs的完整时间和空间库尚未建立。哺乳动物心脏由两组密切相关的心脏祖细胞发育而来，第一心野（FHF）产生左心室（LV），第二心野（SHF）产生右心室（RV）和流出道（OFT）。为了研究miRNA在控制这些谱系发育中的作用，我们使用了不同的遗传标记来开发双色转基因小鼠系统。因此，我们能够从体外分化的胚胎和胚胎干细胞中纯化FHF和SHF祖细胞，并鉴定出一组在两种心脏谱系中差异表达的miRNA。值得注意的是，我们鉴定了miR 200 a和miR 200 b（miR 200），这两种以多顺反子方式转录的密切相关的miRNAs，作为发育中心脏内早期FHF祖细胞特异性的第一种miRNAs，并且在初步实验中证明它们似乎在该谱系的正常发育中起关键作用。我们假设miR 200通过促进FHF祖细胞扩增和分化以及抑制向其他谱系的定向分化来调节心脏发育。我们进一步假设miR 200通过控制特定的靶基因发挥功能，并且是成熟哺乳动物心脏正常形态发生和功能所必需的。为了验证这一点，我们提出了以下具体目标：1）确定miR 200是否通过支持中胚层分化和抑制内胚层和外胚层分化来促进FHF发育; 2）确定miR 200控制FHF发育的机制; 3）确定miR 200在胚胎发育期间的作用。这里开发的工具和理解将有助于心脏再生疗法的科学基础。心脏病每年影响数百万美国人，是美国住院的主要原因。了解心脏是如何发育的将有助于我们了解心脏是如何患病的。这项研究将为未来如何诊断和治疗心脏出生缺陷和成人疾病提供线索。