NUCLEAR FACTOR KAPPA BETA AND INITIATION OF THE ATHEROSC
核因子 KAPPA Beta 和动脉粥样硬化的引发
基本信息
- 批准号:7056678
- 负责人:
- 金额:$ 36.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-04-01 至 2007-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by the applicant):
Atherosclerosis is a major cause of morbidity and mortality among both men and
women. Multiple systemic risk factors, including hypertension, diabetes
mellitus, smoking, and 1ipoprotein disorders are involved in the pathogenesis
of this chronic inflammatory disease of arteries, but to date, it has not been
possible to associate the risk factors with common pathogenic mechanism.
Recent evidence suggests that a small group of transcription factors may be
critical in linking the diverse risk factors to the initiation of the
atherosclerotic lesion.
This project emphasizes one of these transcription factors, nuclear factor-kappaB
(NF-kappaB), whose activation has been linked to the onset of
atherosclerosis through a remarkable series of correlations. These include
observations that activated endothelial NF-kappaB is found predominately in
atherosclerotic lesions where NF-kappaB-dependent endothelial genes are also
selectively expressed; atherosclerosis develops in response to diverse stimuli
that share the ability to create oxidant stress and activate the NF-kappaB
system; several agents inhibiting lesion formation also act as antioxidants
and stabilize NF-kappaB and; atherosclerotic lesions form at distinct regions
of the arterial tree, especially at or near branch points or major curvatures
where the endothelial NF-kappaB system is selectively activated.
Although these correlations are provocative, there is no direct evidence
demonstrating that NF-kappaB activation is necessary or sufficient for
atherosclerosis or for defining lesion-prone regions. The goal of this
proposal, therefore, is to determine the role of endothelial NF-kappaB in
initiation of the atherosclerotic lesion. Unfortunately, loss of function
mutants of several NF-kappaB system components in mice present significant
developmental abnormalities precluding their use for studies of
atherosclerosis. In this application, strategies using conditional mouse
genetics are proposed to avoid this complication and test the hypothesis that
the NF-kappaB system plays a key role in the formation of the early
atherosclerotic lesion. In the First Specific Aim, the LDLR-/- mouse model of
atherosclerosis will be used to determine if NF-kappaB expression is required
for early lesion formation in vivo. These studies utilize the Cre-loxP system
to achieve endothelial -restricted conditional mutation of NF-kappaB system
components. In the Second Specific Aim, we will determine if dysregulated
expression in endothelium of a gene that normally inhibits NF-kappaB
activation alters early lesion formation in LDLR-/- mice. These studies will
use tetracycline-regulated transgene expression to generate mice with
inducible and endothelial-restricted expression of an inhibitor of NF-kappaB
activation. In the Third Specific Aim, we will determine if NF-kappaB
signaling plays a role in specifying lesion prone and lesion resistant regions
of aorta in LDLR-/- mice. Taken together these studies should determine if
the NF-kappaB system is necessary and/or sufficient for the initiation of the
atherosclerotic lesion.
描述(由申请人提供):
动脉粥样硬化是男性和女性发病率和死亡率的主要原因。
妇女多种全身性风险因素,包括高血压、糖尿病
糖尿病、吸烟和脂蛋白紊乱参与了发病机制
这种慢性动脉炎性疾病,但到目前为止,它还没有
这些危险因素可能与共同的致病机制有关。
最近的证据表明,一小群转录因子可能是
关键是将各种风险因素与启动
动脉粥样硬化病变
该项目强调这些转录因子之一,核因子-κ B
(NF-kappaB),其激活与
动脉粥样硬化通过一系列显著的相关性。这些包括
观察到活化的内皮NF-κ B主要在
动脉粥样硬化病变,其中NF-κ B依赖性内皮基因也是
选择性表达;动脉粥样硬化的发展对不同的刺激
共同产生氧化应激并激活NF-κ B的能力
系统;几种抑制病变形成的药物也起抗氧化剂的作用
并稳定NF-κ B,动脉粥样硬化病变在不同区域形成
动脉树的,尤指在或靠近分支点或主要弯曲处
其中内皮NF-κ B系统被选择性激活。
尽管这些相关性具有挑衅性,但没有直接证据表明
证明NF-κ B活化是必要的或足够的,
动脉粥样硬化或用于定义病变倾向区域。这个目标
因此,我们的建议是确定内皮细胞NF-κ B在
动脉粥样硬化病变的开始。不幸的是,功能丧失
小鼠中几种NF-κ B系统组分的突变体呈现显著的
发育异常,使其无法用于研究
动脉粥样硬化在这个应用程序中,策略使用条件鼠标
遗传学被提出来避免这种复杂性,并测试假设,
NF-kappaB系统在早期的形成中起着关键作用,
动脉粥样硬化病变在第一个具体目标中,LDLR-/-小鼠模型
动脉粥样硬化将用于确定是否需要NF-κ B表达
用于体内早期损伤形成。这些研究利用Cre-loxP系统
实现NF-κ B系统的内皮限制性条件突变
件.在第二个具体目标中,我们将确定是否失调
正常情况下抑制NF-κ B的基因在内皮中的表达
活化改变LDLR-/-小鼠中的早期损伤形成。这些研究将
使用四环素调节的转基因表达产生小鼠,
NF-κ B抑制剂诱导型和内皮限制型表达
activation.在第三个具体目标中,我们将确定NF-κ B是否
信号传导在指定易损伤区域和抗损伤区域中起作用
LDLR-/-小鼠的主动脉。综合这些研究,
NF-κ B系统是启动免疫反应所必需的和/或足够的。
动脉粥样硬化病变
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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{{ truncateString('Tucker O Collins', 18)}}的其他基金
Pathobiology of the Developing Cardiovascular System
心血管系统发育的病理学
- 批准号:
7084550 - 财政年份:2005
- 资助金额:
$ 36.96万 - 项目类别:
Pathobiology of the Developing Cardiovascular System
心血管系统发育的病理学
- 批准号:
6845019 - 财政年份:2005
- 资助金额:
$ 36.96万 - 项目类别:
The SCAN Family: Characterization of ZNF174
SCAN 系列:ZNF174 的表征
- 批准号:
6689558 - 财政年份:2002
- 资助金额:
$ 36.96万 - 项目类别:
The SCAN Family: Characterization of ZNF174
SCAN 系列:ZNF174 的表征
- 批准号:
6552994 - 财政年份:2002
- 资助金额:
$ 36.96万 - 项目类别:
The SCAN Family: Characterization of ZNF174
SCAN 系列:ZNF174 的表征
- 批准号:
6836081 - 财政年份:2002
- 资助金额:
$ 36.96万 - 项目类别:
The SCAN Family: Characterization of ZNF174
SCAN 系列:ZNF174 的表征
- 批准号:
6640604 - 财政年份:2002
- 资助金额:
$ 36.96万 - 项目类别:
NUCLEAR FACTOR KAPPA BETA AND THE INITIATION OF THE ATHEROSCLEROTIC LESION
核因子 Kappa Beta 与动脉粥样硬化病变的发生
- 批准号:
6477453 - 财政年份:2001
- 资助金额:
$ 36.96万 - 项目类别: