MECHANISM OF CYTOCHROME P450 GENE EXPRESSION IN THE HYPEROXIC DEVELOPING LUNG
高氧发育肺细胞色素P450基因表达机制
基本信息
- 批准号:5213110
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:RNA arachidonate cimetidine complementary DNA cytochrome P450 endotoxins enzyme activity free radicals fusion gene gene expression genetic transcription growth /development hyperoxia in situ hybridization lung messenger RNA newborn animals nucleic acid sequence oxygen tension polymerase chain reaction sheep tissue /cell culture transfection
项目摘要
Oxygen exposure increases lung oxidant production and causes acute
microvascular injury which can lead to fatal pulmonary edema. Although
much is known about the regulation of anti-oxidant defenses, the
mechanisms, sites and regulation of oxidant production in the hyperoxic
lung are uncertain. In previous work, we defined the physiologic and
biochemical changes which occur in the lamb lung during oxygen exposure.
We demonstrated that oxygen exposure increases lung cytochrome P450 amount
and activity of two potential microsomal oxidant sources, P450 IA1 and
IIB1. Treatment of lambs with either of two chemically dissimilar P450
inhibitors significantly reduced hyperoxic lung injury in vivo.
Immunocytochemical data indicate that lamb lung endothelial cells contain
cytochrome P450 enzymes. These data strongly support the general
hypothesis that cytochrome P450-derived oxidants are involved in the
pathogenesis of acute pulmonary oxygen toxicity in lambs.
The objective of this proposal is to extend our physiologic and biochemical
studies by applying the techniques of molecular and cell biology to
understand the mechanisms by which oxygen exposure increases lung P450.
Preliminary data are presented which indicate that the hyperoxia-induced
increases in lung P450 IIB1 and IA1 activities in vivo are preceded by an
increase in their respective RNA's. Liver RNA levels for P450 are
unaffected by oxygen exposure in vivo. We also demonstrate positive
regulation of P450 IA1 by increased oxygen tension using cultured cells
which have been stably transfected with a fusion gene containing the full-
length mouse P450 IA1 5' flanking region.
The proposal outlines a series of experiments in vivo and in cultured lung
cells using rodent nucleotide probes to measure changes in steady-state
lung P450 RNA levels following treatment with varying concentrations of
oxygen, alone and in the presence of agents which influence lung P450
levels. We will also isolate full-length cDNA clones encoding lamb lung
P450 genes IA1 and IIB1 and use them to identify their 5' flanking regions
in genomic DNA. Then, fusion genes containing the 5' flanking regions
linked to reporter genes will be constructed and used in transfection
experiments to test the hypothesis that lamb lung P450 gene expression is
positively regulated in specific lung cells either directly or indirectly
by increases in ambient oxygen tension. We will also construct homologous
nucleotide probes and use them to localize P450-specific RNA in situ.
These studies will lead to important new insights into the regulation of
genes which encode oxidant-producing enzymes in the developing lung and may
also serve as a model system to study how small molecules regulate gene
expression in higher eukaryotes. In addition, these studies may lead to
the development of safe and effective methods to reduce the oxidant stress
of oxygen exposure in patients with lung diseases who require treatment
with high concentrations of oxygen.
氧气暴露会增加肺部氧化剂的产生,引起急性
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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THOMAS A HAZINSKI其他文献
THOMAS A HAZINSKI的其他文献
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{{ truncateString('THOMAS A HAZINSKI', 18)}}的其他基金
RELATIONSHIP BETWEEN ENDOTOXEMIA AND LUNG INJURY IN NEWBORN INFANTS
新生儿内毒素血症与肺损伤之间的关系
- 批准号:
3909483 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISM OF CYTOCHROME P450 GENE EXPRESSION IN THE HYPEROXIC DEVELOPING LUNG
高氧发育肺细胞色素P450基因表达机制
- 批准号:
3735944 - 财政年份:
- 资助金额:
-- - 项目类别:
RELATIONSHIP BETWEEN ENDOTOXEMIA & LUNG INJURY IN NEWBORN INFANTS
内毒素血症之间的关系
- 批准号:
3953235 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISM OF CYTOCHROME P450 GENE EXPRESSION IN THE HYPEROXIC DEVELOPING LUNG
高氧发育肺细胞色素P450基因表达机制
- 批准号:
3779744 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISM OF CYTOCHROME P450 GENE EXPRESSION IN THE HYPEROXIC DEVELOPING LUNG
高氧发育肺细胞色素P450基因表达机制
- 批准号:
3757819 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISM OF CYTOCHROME P450 GENE EXPRESSION IN THE HYPEROXIC DEVELOPING LUNG
高氧发育肺细胞色素P450基因表达机制
- 批准号:
3843558 - 财政年份:
- 资助金额:
-- - 项目类别:
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