HEART DEVELOPMENT AND GENETICS

心脏发育和遗传学

基本信息

  • 批准号:
    2857819
  • 负责人:
  • 金额:
    $ 25.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1993
  • 资助国家:
    美国
  • 起止时间:
    1993-01-01 至 2000-12-31
  • 项目状态:
    已结题

项目摘要

The goal of this project is to understand the unitary steps of cardiovascular development. The approach combines genetics, molecular biology, and embryology. We have shown that the zebrafish heart and vasculature are amenable to genetic dissection, accessible to embryological manipulation in a transparent embryo, and analogous to the mammalian through the heart tube stage. During the two years of the current grant, we have completed the largest genetic screen for cardiovascular mutations ever undertaken. We have identified 124 recessive lethal mutations which specifically disrupt cardiovascular development. For example, we have mutants which lack endocardium or valves, those which have hearts that are too small or too large, and those constituted of a single chamber. In addition, by single-cell tracer injection, we have discovered the location of a heart field in the blastula and identified cells that give rise to both myocardium and endocardium. Specific Aim 1 is to complete the complementation analysis of the different mutations and to map the mutations onto our zebrafish genome map. This is the first step towards cloning of the mutant genes. Specific Aim 2 is to analyze the embryonic heart field and lineage tree of cardiac progenitors. In particular, our evidence suggests that there is a common progenitor cell in the ventral-marginal blastula for myocardium, endocardium, endothelium, and blood and we need to test this hypothesis by defining the sublineages. We have evidence that the heart field of the blastula is spatially determined, at least in part, by the divergent homebox gene tinman, and we will assess this thesis by ectopic overexpression combined with cell tracking. Specific Aim 3 focuses upon the two mutations we discovered that are of clear-cut interest to the patterning of the vasculature. Each perturbs genesis of a specific stretch of endothelium: (a) cloche abolishes the endocardium (and possibly some head endothelium). Our hypothesis is that it blocks endocardial progenitors during their formation ow migration; (b) gridlock blocks vessel assembly in the region where the two dorsal aortae merge to become a single aorta. Many attributes of this mutant resemble the human disease coarctation of the aorta. Our primary question is whether the defects are in the endothelial cells or in the microenvironment. The mutations provide a resource for the entire community of cardiovascular scientists. They define decisions in vascular development. We hope that they can render more accessible the fashioning of higher order complex organs such as the heart, and can be used to define interacting genes. The identification of the earliest heart field is a first step towards definition of the molecular nature of the earliest cardiac progenitors. The endothelial mutations, in particular, provide the first evidence for discrete regional patterning in endothelial assembly. In medical terms, the mutations provide indices to the key unitary steps of cardiac assembly, ones which may go awry in some of the common congenital and adult heart diseases. Ultimately, these will lead to the cloning of the new genes relevant to fashioning cardiovasculature and which underlie propensities to cardiovascular illness.
这个项目的目标是理解的统一步骤

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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MARK C FISHMAN其他文献

MARK C FISHMAN的其他文献

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{{ truncateString('MARK C FISHMAN', 18)}}的其他基金

A day in the life of a larval zebrafish. Characterization and Modeling of Behavioral Dynamics and Interoceptive Homeostasis
斑马鱼幼虫生命中的一天。
  • 批准号:
    10686986
  • 财政年份:
    2017
  • 资助金额:
    $ 25.44万
  • 项目类别:
A day in the life of a larval zebrafish. Characterization and Modeling of Behavioral Dynamics and Interoceptive Homeostasis
斑马鱼幼虫生命中的一天。
  • 批准号:
    10525433
  • 财政年份:
    2017
  • 资助金额:
    $ 25.44万
  • 项目类别:
Physiological Genomics of the Zebrafish Heart
斑马鱼心脏的生理基因组学
  • 批准号:
    6503726
  • 财政年份:
    2002
  • 资助金额:
    $ 25.44万
  • 项目类别:
GENETIC DISSECTION OF HEART MORPHOGENESIS IN ZEBRAFISH
斑马鱼心脏形态发生的基因解剖
  • 批准号:
    2892892
  • 财政年份:
    1999
  • 资助金额:
    $ 25.44万
  • 项目类别:
GENETIC DISSECTION OF HEART MORPHOGENESIS IN ZEBRAFISH
斑马鱼心脏形态发生的基因解剖
  • 批准号:
    6390463
  • 财政年份:
    1999
  • 资助金额:
    $ 25.44万
  • 项目类别:
GENETIC DISSECTION OF HEART MORPHOGENESIS IN ZEBRAFISH
斑马鱼心脏形态发生的基因解剖
  • 批准号:
    6184840
  • 财政年份:
    1999
  • 资助金额:
    $ 25.44万
  • 项目类别:
CONSTRUCTION OF A GENETIC LINKAGE MAP OF ZEBRAFISH
斑马鱼遗传连锁图谱的构建
  • 批准号:
    2774171
  • 财政年份:
    1998
  • 资助金额:
    $ 25.44万
  • 项目类别:
CONSTRUCTION OF A GENETIC LINKAGE MAP OF ZEBRAFISH
斑马鱼遗传连锁图谱的构建
  • 批准号:
    6124712
  • 财政年份:
    1998
  • 资助金额:
    $ 25.44万
  • 项目类别:
CONSTRUCTION OF A GENETIC LINKAGE MAP OF ZEBRAFISH
斑马鱼遗传连锁图谱的构建
  • 批准号:
    6329432
  • 财政年份:
    1998
  • 资助金额:
    $ 25.44万
  • 项目类别:
CONSTRUCTION OF A GENETIC LINKAGE MAP OF ZEBRAFISH
斑马鱼遗传连锁图谱的构建
  • 批准号:
    2655568
  • 财政年份:
    1994
  • 资助金额:
    $ 25.44万
  • 项目类别:

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