Regulation of Proinflammatory Signaling Pathways by CFTR
CFTR 对促炎信号通路的调节
基本信息
- 批准号:6433785
- 负责人:
- 金额:$ 27.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-06-15 至 2005-01-31
- 项目状态:已结题
- 来源:
- 关键词:Pseudomonas aeruginosa cell line chloride channels confocal scanning microscopy cystic fibrosis genetic promoter element immunogenetics immunopharmacology immunoregulation inflammation interleukin 8 intracellular transport microarray technology molecular pathology pharmacogenetics protein structure function respiratory infections transfection
项目摘要
DESCRIPTION (provided by applicant): The principal goal of this proposal is to
identify the intracellular signaling pathways in the lung that mediate the
chronic processes of inflammation and infection associated with cystic fibrosis
(CF). Preliminary data indicate that airway epithelial cell lines derived from
CF trachea secrete massive levels of pro-inflammatory IL8. Consistently, gene
therapy with CFTR, or drug therapy with CPX, suppresses baseline levels of IL8
secretion, while still allowing physiological IL8 secretion in response to the
presence of bacteria. In normal epithelial cells, IL8 secretion is mediated by
activation of the NFkB pathway, and pharmacogenomic studies indicate that a
subset of NFkB pathway genes parallel the secretion of IL8 as a function of
CFTR, CPX and exposure to P. aeruginosa. We have therefore hypothesized that
the mechanism by which CFTR suppresses IL8 secretion from CF epithelial cells
is by direct action on a pro-inflammatory intracellular signaling pathway. We
wish to identify and study this pathway, and propose the following Specific
Aims. Aim #1: To determine the signaling pathways by which CFTR and CPX
suppress IL8 secretion from CF epithelial cells. We will use cDNA microarrays
to identify genes whose expression is altered by CFTR, or by the presence of
CPX. Aim #2: To identify the molecular mechanisms by which CFTR or CPX permit
CF epithelial cells to respond physiologically to the presence of Pseudomonas
aeruginosa. We will identify cis-acting elements within the IL8 promoter which
mediate activation or suppression by CFTR, CPX and P. aeruginosa. Aim #3: To
identify subdomains in CFTR that suppress IL8 secretion from CF epithelial
cells. We will prepare viral vector constructs expressing CFTR from which
different subdomains have been deleted, and identify the CFTR domain(s)
required for suppression of IL8 secretion. Expectations, Innovation and Impact:
Our expectations are that this research will generate valuable new knowledge
that will be useful for the development of novel therapies for CF. The proposed
hypothesis-driven research is innovative because biochemistry and
hypothesis-driven pharmacogenomics have not previously been used in this way to
investigate a single gene disease such as cystic fibrosis. The impact of this
research will be to identify novel pathways by which CFTR affects the ability
of lung epithelial cells to respond to bacterial assault.
描述(申请人提供):本提案的主要目标是
确定肺中介导
与囊性纤维化相关的慢性炎症和感染过程
(CF)。初步数据表明,来源于
CF气管分泌大量水平的促炎性IL8。一致性,基因
CFTR治疗或CPX药物治疗可抑制IL 8的基线水平
分泌,同时仍然允许响应于所述刺激的生理性IL 8分泌。
细菌的存在。在正常上皮细胞中,IL 8的分泌是由
NFkB通路的激活,药物基因组学研究表明,
NFkB途径基因的子集平行于IL 8的分泌,作为
CFTR、CPX和铜绿假单胞菌暴露。因此,我们假设,
CFTR抑制CF上皮细胞分泌IL 8的机制
是通过直接作用于促炎细胞内信号传导途径。我们
我希望确定和研究这一途径,并提出以下具体建议
目标。目的#1:确定CFTR和CPX的信号通路
抑制CF上皮细胞分泌IL 8。我们将使用cDNA微阵列
为了鉴定其表达被CFTR改变的基因,或被CFTR存在改变的基因,
CPX目的#2:确定CFTR或CPX允许的分子机制
CF上皮细胞对假单胞菌存在的生理反应
铜绿。我们将鉴定IL 8启动子内的顺式作用元件,
介导CFTR、CPX和铜绿假单胞菌的激活或抑制。目标3:
鉴定CFTR中抑制CF上皮细胞分泌IL 8的亚结构域
细胞我们将制备表达CFTR的病毒载体构建体,
删除了不同的子域,并确定CFTR域
抑制IL8分泌所需的。期望、创新和影响:
我们的期望是,这项研究将产生有价值的新知识
这将有助于开发CF的新疗法。拟议
假设驱动的研究是创新的,因为生物化学和
假设驱动药物基因组学以前没有以这种方式用于
研究单基因疾病,如囊性纤维化。这样做的影响
研究将确定CFTR影响能力的新途径,
肺上皮细胞对细菌攻击的反应。
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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Harvey Bruce Pollard其他文献
Harvey Bruce Pollard的其他文献
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{{ truncateString('Harvey Bruce Pollard', 18)}}的其他基金
COVID-19 airway inflammation is due to Spike inhibition of CFTR signaling
COVID-19 气道炎症是由于 CFTR 信号的 Spike 抑制所致
- 批准号:
10566710 - 财政年份:2023
- 资助金额:
$ 27.34万 - 项目类别:
Regulation of Proinflammatory Signaling Pathways in CFTR
CFTR 中促炎信号通路的调节
- 批准号:
7143989 - 财政年份:1998
- 资助金额:
$ 27.34万 - 项目类别:
Regulation of Proinflammatory Signaling Pathways in CFTR
CFTR 中促炎信号通路的调节
- 批准号:
7275391 - 财政年份:1998
- 资助金额:
$ 27.34万 - 项目类别:
PHOSPHOLIPIDS AS CHEMICAL CHAPERONES FOR CFTR
磷脂作为 CFTR 的化学伴侣
- 批准号:
2628917 - 财政年份:1998
- 资助金额:
$ 27.34万 - 项目类别:
Regulation of Proinflammatory Signaling Pathways by CFTR
CFTR 对促炎信号通路的调节
- 批准号:
6704704 - 财政年份:1998
- 资助金额:
$ 27.34万 - 项目类别:
Regulation of Proinflammatory Signaling Pathways in CFTR
CFTR 中促炎信号通路的调节
- 批准号:
7477883 - 财政年份:1998
- 资助金额:
$ 27.34万 - 项目类别:
Regulation of Proinflammatory Signaling Pathways in CFTR
CFTR 中促炎信号通路的调节
- 批准号:
7671433 - 财政年份:1998
- 资助金额:
$ 27.34万 - 项目类别:
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