Heart Development and Genetics

心脏发育和遗传学

• 批准号: 6537058
• 负责人: MARK C FISHMAN
• 金额: $ 30.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537058
• 关键词: angiogenesis; developmental genetics; embryology; gene expression; gene mutation; genetic mapping; heart; histogenesis; molecular cloning; zebrafish

DESCRIPTION (provided by applicant): This work represents a continuation of our program using zebrafish genetics and embryology to understand the earliest embryonic steps in fashioning the cardiovascular system. We focus here in particular upon the molecular pathways for assembly of the first artery and vein in the embryo. This process, termed vasculogenesis, is not well understood. We use as linchpins for this work two mutations we discovered in a zebrafish genetic screen. gridlock is a mutation affecting the aorta. We positionally cloned the gridlock gene. It is expressed in the aorta but not the vein, and is a novel member of the HES family of transcription factors. The second mutation, cloche , is a mutation that prevents formation of both blood and vessels, appearing to act as an essential element in generation of the elusive hemangioblast, a cell proposed to give rise both to the earliest blood and vessels in the embryo. Specific Aim 1: We will use laser-activated dye uncaging to define the origin and migratory track of angioblasts giving rise to the first artery and vein, both in wild-type and mutants defective in vasculogenesis. Specific Aim 2: In other systems, HES genes are known to function in driving cell fate decisions, and are the downstream effectors of the cell surface receptor, Notch. We propose that gri acts in a pathway which drives angioblasts to become pre-arterial or pre-venous even prior to generation of functioning vessels, and to do so as part of a pathway involving the cell surface Notch receptor. We will test this hypothesis by examination of the cellular and molecular effects of increasing or reducing grl and molecular components of the Notch cascade. Specific Aim 3: We will complete the positional cloning of cloche, and begin to examine its mechanism of action. This work defines pathways critical to normal vessel formation. These genes will be of importance as candidate genes for congenital vascular disorders such as aortic coarctation. It will also be of importance to examine these developmental pathways in the context of adult vessel injury, repair, and collateralization.

描述(由申请人提供)：这项工作是我们的 利用斑马鱼遗传学和胚胎学了解最早的 形成心血管系统的胚胎步骤。我们在这里专注于 特别是关于第一动脉和第一动脉组装的分子途径 胚胎中的静脉。这个被称为血管生成的过程并不是很好 明白了。我们使用两个突变作为这项工作的关键，我们在一个 斑马鱼基因筛查。交通堵塞是一种会影响大动脉的突变。我们 定位克隆了塞车基因。它在主动脉中表达，但不在 VINE，是HES转录因子家族的新成员。这个 第二种突变是loche，这是一种阻止两种血液形成的突变。 和血管，似乎是产生 难以捉摸的血管母细胞，一种被认为是产生最早血液的细胞 和胚胎中的血管。 具体目标1：我们将使用激光激活的染料去除来确定原点 以及形成第一动静脉的血管母细胞的迁移轨迹， 在血管生成缺陷的野生型和突变体中都是如此。具体目标2：In 在其他系统中，已知HES基因在决定细胞命运方面发挥作用， 是细胞表面受体Notch的下游效应器。我们 认为GRI在一条途径中起作用，促使血管母细胞 动脉前或静脉前，甚至在功能血管生成之前，以及 这是涉及细胞表面Notch受体的途径的一部分。我们 将通过检查细胞和分子效应来检验这一假说 增加或减少GRL和Notch级联的分子组件。 具体目标三：完成Cloche的位置克隆，并开始 研究其作用机制。 这项工作定义了对正常血管形成至关重要的途径。这些基因 将作为先天性血管疾病的候选基因具有重要意义 作为主动脉缩窄。同样重要的是要研究这些问题 成人血管损伤、修复和修复的发育途径 抵押品。

项目成果

A reference cross DNA panel for zebrafish (Danio rerio) anchored with simple sequence length polymorphisms.

斑马鱼 (Danio rerio) 的参考交叉 DNA 组合，锚定于简单的序列长度多态性。

• DOI: 10.1242/dev.123.1.451
• 发表时间: 1996
• 期刊: Development (Cambridge, England)
• 作者: Knapik,EW;Goodman,A;Atkinson,OS;Roberts,CT;Shiozawa,M;Sim,CU;Weksler-Zangen,S;Trolliet,MR;Futrell,C;Innes,BA;Koike,G;McLaughlin,MG;Pierre,L;Simon,JS;Vilallonga,E;Roy,M;Chiang,PW;Fishman,MC;Driever,W;Jacob,H
• 通讯作者: Jacob,H

Cardiovascular development in the zebrafish. I. Myocardial fate map and heart tube formation.

• DOI: 10.1242/dev.119.1.31
• 发表时间: 1993-09
• 期刊: Development
• 影响因子: 4.6
• 作者: D. Stainier;Robert K. K. Lee-Robert-K.-K.-Lee-2107716099;M. Fishman

Pre-pattern in the pronephric kidney field of zebrafish.

斑马鱼前肾区的预模式。

• DOI: 10.1242/dev.128.12.2233
• 发表时间: 2001
• 期刊: Development (Cambridge, England)
• 作者: Serluca,FC;Fishman,MC
• 通讯作者: Fishman,MC

Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation.

斑马鱼锡曼同源物界定心脏区域并启动心肌分化。

• DOI: 10.1242/dev.122.12.3809
• 发表时间: 1996
• 期刊: Development (Cambridge, England)
• 作者: Chen,JN;Fishman,MC
• 通讯作者: Fishman,MC

Mutations affecting development of zebrafish digestive organs.

影响斑马鱼消化器官发育的突变。

• DOI: 10.1242/dev.123.1.321
• 发表时间: 1996
• 期刊: Development (Cambridge, England)
• 作者: Pack,M;Solnica-Krezel,L;Malicki,J;Neuhauss,SC;Schier,AF;Stemple,DL;Driever,W;Fishman,MC
• 通讯作者: Fishman,MC