HEART DEVELOPMENT AND GENETICS
心脏发育和遗传学
基本信息
- 批准号:2637995
- 负责人:
- 金额:$ 24.46万
- 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 1999-12-31
- 项目状态:已结题
- 来源:
- 关键词:
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.
这个项目的目标是了解的单一步骤,
心血管发育该方法结合了遗传学、分子学
生物学和胚胎学。我们已经证明了斑马鱼的心脏和
脉管系统可以进行遗传解剖,
在透明胚胎中的胚胎学操作,并且类似于
哺乳动物通过心管阶段。在两年的时间里,
目前,我们已经完成了最大的基因筛选,
心血管变异的研究我们发现了124个隐性基因
致命的突变,专门破坏心血管发育。
例如,我们有缺乏内分泌系统或瓣膜的突变体,
有太小或太大的心,那些由一个
单室此外,通过单细胞示踪剂注射,我们有
发现了囊胚中心脏区域的位置,
产生心肌和心内膜的细胞。具体目标1是
完成不同突变的互补分析,
将突变映射到我们的斑马鱼基因组图谱上。这是第一步
突变基因的克隆。具体目标2是分析
胚胎心脏野和心脏祖细胞谱系树。在
特别是,我们的证据表明,有一个共同的祖细胞,
在心肌、内皮细胞、内皮细胞、
我们需要通过定义亚系来验证这个假设。
我们有证据表明囊胚的心脏区域在空间上
决定,至少部分,由不同的homebox基因tinman,我们
将通过异位过表达结合细胞凋亡来评估这一论文。
跟踪.具体目标3关注我们发现的两种突变,
对脉管系统的形成有着明确的意义。每个
干扰内皮细胞特定伸展的发生:(a)钟形细胞
消除了内皮细胞(可能还有一些头部内皮细胞)。我们
一种假说是,它在内皮祖细胞生长过程中阻断了它们的生长。
地层流动;(B)交通堵塞阻碍了该区域的船只组装
两条背侧动脉合并成一条主动脉许多
这种突变体的属性类似于人类疾病的缩窄,
主动脉我们的主要问题是缺陷是否在内皮细胞
细胞或微环境中。
这些突变为整个人类社会提供了一种资源,
心血管科学家它们定义了血管发育的决定。
我们希望他们能使更高的时尚更容易获得
复杂的器官,如心脏,并可用于定义
相互作用的基因最早的心脏领域的鉴定是一个
第一步,定义最早的
心脏祖细胞特别是内皮细胞突变,
内皮组装中离散区域模式的第一个证据。
在医学术语中,突变为关键的单一步骤提供了指标,
心脏组装,那些可能会出错,在一些常见的
先天性和成人心脏病。最终,这些将导致
克隆与形成心血管系统相关的新基因,
这是心血管疾病倾向的基础。
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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 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:
$ 24.46万 - 项目类别:
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