MOLECULAR GENETICS OF HUMAN BMP-4 IN FOP
FOP 中人类 BMP-4 的分子遗传学
基本信息
- 批准号:6016880
- 负责人:
- 金额:$ 30.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-06-01 至 2001-05-31
- 项目状态:已结题
- 来源:
- 关键词:DNA binding protein DNA footprinting blood chemistry bone development disorder clinical research developmental genetics gel mobility shift assay gene expression gene mutation genetic markers genetic promoter element genetic regulatory element human genetic material tag human subject immunocytochemistry linkage mapping messenger RNA nuclear runoff assay osteogenesis pathologic ossification polymerase chain reaction progressive myositis ossificans protein structure function regulatory gene
项目摘要
The embryogenesis and regeneration of the skeleton are complex
developmental events dependent on the successful induction of
endochondral osteogenesis. Little is known, however, about the
genetic control of bone induction. Bone morphogenetic proteins
(BMPs) are members of a highly conserved family of molecules
involved in the regulation of embryonic pattern formation and
osteogenesis. Recombinant human BMP-4 can induce the entire
developmental program of endochondral osteogenesis in an ectopic
site in a manner identical to that seen in the autosomal dominant
genetic disorder, fibrodysplasia ossificans progressive (FOP). FOP
is a progressively disabling condition characterized by congenital
malformations of the toes and disordered temporal and spatial
induction of endochondral osteogenesis at ectopic sites. BMP-4
messenger RNA and proteins uniquely over-expressed
inlymphocytes from patients who have FOP. These data indicate
that over expression of BMP-4, a potent bone-inducing morphogen,
is associated with disabling ectopic osteogenesis in man. Tow
related hypotheses provide the focus for our longterm goals; First,
the molecular structure and function of the human BMP-4 gene
provides fundamental insight into the genetic regulation of
endochondral bone induction and pattern formation in humans;
second, BMP-4 is the prime candidate gene for FOP; and the
molecular structure and/or regulatory control of that gene is
abnormal in patients who have FOP. To address these hypothesis,
we intend to: 1. Define the regulatory regions of the human BMP-4
gene by reporter gene expression assays. 2. Identify DNA-binding
proteins for the BMP-4 gene in normal and FOP cells by gel
mobility shift and footprinting assays using nuclear protein extracts
from FOP and non-FOP cells. 3. Examine the rate of BMP-4
transcript initiation and mRNA stability in FOP cells relative to
control cells by nuclear run-on and transcription inhibition
experiments. 4. Examine the expression of BMP type I and type II
receptors in FOP cells by RT-PCR and immunohistochemistry. 5.
Identify genetic markers that are closely linked to the BMP-4 gene
locus and utilize these markers to establish or exclude genetic
linkage of the BMP-4 gene with FOP. Analysis of the regulatory
control of the human BPM-4 gene will foster that longterm goal of
elucidating basic mechanisms of normal and disordered bone
induction, and of designing rational molecular diagnostic and
treatment strategies for a wide range of developmental disorders of
the skeleton in humans.
骨骼的胚胎发生和再生是复杂的
发展事件依赖于成功诱导
软骨内成骨 然而,人们对它知之甚少。
骨诱导的遗传控制。 骨形态发生蛋白
骨形成蛋白(BMPs)是一个高度保守的分子家族的成员,
参与胚胎模式形成的调节,
成骨 重组人BMP-4可以诱导整个
异位软骨内成骨的发育程序
位点的方式与常染色体显性遗传中所见相同
进行性骨化性纤维发育不良(FOP)。FOP
是一种逐渐致残的疾病,
脚趾畸形和时空紊乱
在异位部位诱导软骨内成骨。 BMP-4
信使RNA和蛋白质独特地过度表达
FOP患者的淋巴细胞中。 这些数据表明
BMP-4的过度表达,一种有效的骨诱导形态原,
与人类异位成骨的失能有关。
相关假设为我们的长期目标提供了焦点;首先,
人BMP-4基因的分子结构和功能
提供了对遗传调控的基本见解,
人类的软骨内骨诱导和模式形成;
第二,BMP-4是FOP的主要候选基因;
该基因分子结构和/或调节控制被
在FOP患者中异常。为了解决这些假设,
我们打算:定义人BMP-4的调控区
基因通过报告基因表达测定。 2.鉴定DNA结合
通过凝胶电泳分析正常和FOP细胞中BMP-4基因的蛋白质
使用核蛋白提取物的迁移率变化和足迹分析
从FOP和非FOP细胞。 3.检测BMP-4的表达率
转录起始和mRNA稳定性
通过核启动和转录抑制控制细胞
实验4.检测I型和II型BMP的表达
通过RT-PCR和免疫组织化学方法检测FOP细胞中受体的表达。5.
识别与BMP-4基因紧密相关的遗传标记
基因座,并利用这些标记来建立或排除遗传
BMP-4基因与FOP的连锁。监管分析
人类BPM-4基因的控制将促进这一长期目标,
阐明正常和紊乱骨骼的基本机制
诱导,设计合理的分子诊断和
一系列发育障碍的治疗策略,
人类的骨架
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
FREDERICK Samuel KAPLAN其他文献
FREDERICK Samuel KAPLAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('FREDERICK Samuel KAPLAN', 18)}}的其他基金
Genetic Linkage Analysis by Mitotic Recombination
通过有丝分裂重组进行遗传连锁分析
- 批准号:
6441323 - 财政年份:2001
- 资助金额:
$ 30.28万 - 项目类别:
Genetic Linkage Analysis by Mitotic Recombination
通过有丝分裂重组进行遗传连锁分析
- 批准号:
6533054 - 财政年份:2001
- 资助金额:
$ 30.28万 - 项目类别:
The Cellular and Molecular Basis of FOP Lesions
FOP 病变的细胞和分子基础
- 批准号:
8331017 - 财政年份:1994
- 资助金额:
$ 30.28万 - 项目类别:
The Cellular and Molecular Basis of FOP Lesions
FOP 病变的细胞和分子基础
- 批准号:
8651418 - 财政年份:1994
- 资助金额:
$ 30.28万 - 项目类别:
MOLECULAR GENETICS OF BMP2 AND 4--FOP CANDIDATE GENES
BMP2和4--FOP候选基因的分子遗传学
- 批准号:
2081096 - 财政年份:1994
- 资助金额:
$ 30.28万 - 项目类别:
MOLECULAR GENETICS OF HUMAN BMP-4 IN FOP
FOP 中人类 BMP-4 的分子遗传学
- 批准号:
2712450 - 财政年份:1994
- 资助金额:
$ 30.28万 - 项目类别:
The Cellular and Molecular Basis of FOP Lesions
FOP 病变的细胞和分子基础
- 批准号:
8241612 - 财政年份:1994
- 资助金额:
$ 30.28万 - 项目类别:
The Cellular and molecular Basis of FOP Lesions
FOP 病变的细胞和分子基础
- 批准号:
8582260 - 财政年份:1994
- 资助金额:
$ 30.28万 - 项目类别:
相似海外基金
DNA footprinting of a plant defense gene family; to support visit by A.M. Yorkin, Department of Genetics, St. Petersburg State University, St. Petersburg, Russia
植物防御基因家族的 DNA 足迹;
- 批准号:
147394-1992 - 财政年份:1993
- 资助金额:
$ 30.28万 - 项目类别:
International: Foreign Researcher (H)