FGD1/CDC42: SIGNAL TRANSDUCTION & DEVELOPMENTAL GENETICS
FGD1/CDC42: SIGNAL TRANSDUCTION & DEVELOPMENTAL GENETICS
批准号:
2889293
负责人:
JEROME L. GORSKI
金额:
$31.74万
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-09-09 至 2001-08-31
关键词:
biological signal transduction developmental genetics embryo /fetus cell /tissue gene expression gene induction /repression gene mutation gene targeting genetic disorder genetically modified animals guanine nucleotide binding protein guanine nucleotide exchange factors guanosinetriphosphatases histogenesis immunocytochemistry laboratory mouse microinjections model design /development molecular cloning polymerase chain reaction protein kinase sex linked trait skeletal disorder stress proteins vertebrate embryology yeast two hybrid system zebrafish
中文摘要
描述:本研究旨在分析黑色素瘤的分子遗传学。
面性发育不良(FGDY),一种X连锁的发育障碍,
对多种骨骼结构的形成产生不利影响,包括
面部、脊柱和四肢远端的元素。负责的基因
对于这种疾病,FGD1编码一种鸟核苷酸交换因子(Egf)。
它特异性地激活了Rho(RAS同源)家族的成员CDC42
P21GTP酶。通过激活CDC42,FGD1刺激成纤维细胞
形成丝状伪足,参与细胞信号传递的细胞骨架元素,
黏附和迁移。通过CDC42,FGD1还激活了
应激激活蛋白激酶(SAPK)信号转导通路
调节细胞的生长和分化。初步研究表明,
FGD1主要在骨骼祖细胞中表达,包括脊椎
软骨前浓缩、颈椎骨化和骨化
颅面部骨骼,受FGDY影响的骨骼。不过,数据也显示,
哺乳动物基因组包含多个FGD1同源物,这一结果表明
FGD1可能是部分冗余的CDC42激活的组成部分
系统。总而言之,累积的数据表明FGD1是一个组件
一种发育调节的信号通路参与细胞
形态和哺乳动物的骨骼发生。
该应用程序的总体目标是开发一个全面的模型
为了进一步阐明FGD/CDC42信号级联在细胞内的作用
哺乳动物的形态发生。为此,杂交和退化
将使用聚合酶链式反应扩增技术分离出更多的FGD1
同源基因;小鼠和斑马鱼FGD基因克隆将用于确定
胚胎发育过程中基因表达的时空模式。
为了提供精确的细胞定位,FGD1定向的抗体将
用于通过免疫细胞化学研究胚胎组织。微量注射和
体外试验将被用于研究分子生物学和
从分子水平上剖析FGD蛋白的功能结构域。双杂交
和其他分子技术将被用来分离和鉴定
FGD1/CDC42信号转导通路的其他组件。
表达重组FGD1蛋白的转基因小鼠将用于研究
FGD1表达异常的发育后果。
将产生FGD缺陷小鼠来研究其发育后果
FGD缺失型。复合FGD缺陷小鼠将产生
检查FGD同系物的功能冗余。这些分析将
为研究FGD/Cdc42信号的分子遗传学提供了一种手段
哺乳动物形态发生中的转导途径。这些分析应该
导致对骨骼形成、信号
转导,以及导致基因多样性的一般原则。
骨瘦如柴。
英文摘要
DESCRIPTION: This research aims to analyze the molecular genetics of
faciogenital dysplasia (FGDY), an X-linked developmental disorder that
adversely affects the formation of multiple skeletal structures including
elements of the face, spine, and distal extremities. The gene responsible
for this disorder, FGD1, encodes a guanine nucleotide exchange factor (GEF)
that specifically activates Cdc42, a member of the Rho (Ras-homology) family
of the p21 GTPases. By activating Cdc42, FGD1 stimulates fibroblasts to
form filopodia, cytoskeletal elements involved in cellular signaling,
adhesion and migration. Through Cdc42, FGD1 also activates the
stress-activated protein kinase (SAPK) signaling cascade, a pathway that
regulates cell growth and differentiation. Preliminary studies show that
FGD1 is primarily expressed in skeletal progenitors including vertebral
precartilagenous condensations, ossifying cervical vertebrae, and ossifying
craniofacial bones, bones affected in FGDY. However, data also shows that
mammalian genomes contain multiple FGD1 homologues, a result that suggests
that FGD1 may be a component of a partially redundant Cdc42 activation
system. Together, the accumulated data indicates that FGD1 is a component
of a developmentally regulated signaling pathway involved in cellular
morphology and mammalian skeletogenesis.
The overall goals of this application are to develop a comprehensive model
to further elucidate the role of the FGD/Cdc42 signaling cascade in
mammalian morphogenesis. To this end, cross-hybridization and degenerate
PCR amplification techniques will be used to isolate additional FGD1
homologues; mouse and zebrafish FGD cDNA clones will be used to determine
the spatial and temporal patterns of gene expression during embryogenesis.
To provide precise cellular localization, FGD1-directed antibodies will be
used to study embryonic tissue by immunocytochemistry. Microinjection and
in vitro assays will be used to study the molecular biology and to
molecularly dissect the functional domains of the FGD proteins. Two-hybrid
and other molecular techniques will be used to isolate and characterize
additional components of the FGD1/Cdc42 signal transduction pathway.
Transgenic mice that express recombinant FGD1 proteins will be used to study
the developmental consequences of dysregulated FGD1 expression.
FGD-deficient mice will be generated to study the developmental consequences
of null FGD genotypes. Compound FGD-deficient mice will be generated to
examine FGD homologues for functional redundancy. These analyses will
provide a means to study the molecular genetics of the FGD/Cdc42 signal
transduction pathway in mammalian morphogenesis. These analyses should
result in a more thorough understanding of skeletogenesis, signal
transduction, and the general principles responsible for the diversity of
skeletal form.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
ISOLATION AND CHARACTERIZATION OF GENES RESPONSIBLE FOR MAMMALIAN DEVELOPMENT
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批准号:6297185
-
项目类别:
-
资助金额:$0.02万
-
财政年份:1998
-
负责人:JEROME L. GORSKI
-
依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
-
批准号:6113504
-
项目类别:
-
资助金额:$0.02万
-
财政年份:1998
-
负责人:JEROME L. GORSKI
-
依托单位:
ISOLATION AND CHARACTERIZATION OF GENES RESPONSIBLE FOR MAMMALIAN DEVELOPMENT
-
批准号:6113454
-
项目类别:
-
资助金额:$0.02万
-
财政年份:1998
-
负责人:JEROME L. GORSKI
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依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
-
批准号:6297172
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项目类别:
-
资助金额:$0.02万
-
财政年份:1998
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负责人:JEROME L. GORSKI
-
依托单位:
FGD1/CDC42: SIGNAL TRANSDUCTION & DEVELOPMENTAL GENETICS
-
批准号:2674010
-
项目类别:
-
资助金额:$30.87万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
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依托单位:
MOLECULAR ANALYSIS AND CLONING OF THE AARSKOG SYNDROME (FGDY) GENE LOCUS
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批准号:6274626
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项目类别:
-
资助金额:$2.15万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
ISOLATION AND CHARACTERIZATION OF GENES RESPONSIBLE FOR MAMMALIAN DEVELOPMENT
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批准号:6244665
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项目类别:
-
资助金额:$2.22万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
FGD1/CDC42: SIGNAL TRANSDUCTION & DEVELOPMENTAL GENETICS
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批准号:6181839
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项目类别:
-
资助金额:$31.01万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
ISOLATION AND CHARACTERIZATION OF GENES RESPONSIBLE FOR MAMMALIAN DEVELOPMENT
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批准号:6274688
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项目类别:
-
资助金额:$2.15万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
FGD1/CDC42: SIGNAL TRANSDUCTION & DEVELOPMENTAL GENETICS
-
批准号:2409016
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项目类别:
-
资助金额:$28.68万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
-
批准号:6274738
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项目类别:
-
资助金额:$2.15万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
MOLECULAR ANALYSIS AND CLONING OF THE AARSKOG SYNDROME (FGDY) GENE LOCUS
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批准号:6244580
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项目类别:
-
资助金额:$2.22万
-
财政年份:1997
-
负责人:JEROME L. GORSKI
-
依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
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批准号:3417677
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项目类别:
-
资助金额:$23.73万
-
财政年份:1991
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负责人:JEROME L. GORSKI
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依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
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批准号:3417675
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项目类别:
-
资助金额:$22.1万
-
财政年份:1991
-
负责人:JEROME L. GORSKI
-
依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
-
批准号:3417676
-
项目类别:
-
资助金额:$23.54万
-
财政年份:1991
-
负责人:JEROME L. GORSKI
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依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
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批准号:2268740
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项目类别:
-
资助金额:$23.74万
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财政年份:1991
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负责人:JEROME L. GORSKI
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依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
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批准号:3324014
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项目类别:
-
资助金额:$10.87万
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财政年份:1988
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负责人:JEROME L. GORSKI
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依托单位:
ANALYSIS & CLONING OF A DEVELOPMENT SKIN LOCUS
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批准号:3324011
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项目类别:
-
资助金额:$8.13万
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财政年份:1988
-
负责人:JEROME L. GORSKI
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依托单位:
ANALYSIS AND CLONING OF A DEVELOPMENTAL SKIN LOCUS
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批准号:3324015
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项目类别:
-
资助金额:$15.47万
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财政年份:1988
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负责人:JEROME L. GORSKI
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依托单位:
MOLECULAR GENETICS TRAINING: RIBOSOMAL GENE EXPRESSION
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批准号:3086958
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项目类别:
-
资助金额:$6.26万
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财政年份:1986
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负责人:JEROME L. GORSKI
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依托单位:
海外基金