In vivo Models of Defensin Activity
防御素活性的体内模型
基本信息
- 批准号:6620934
- 负责人:
- 金额:$ 3.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-02-01 至 2003-08-31
- 项目状态:已结题
- 来源:
- 关键词:Escherichia coli Listeria Salmonella typhimurium antibacterial antibody bacteria infection mechanism bacterial cytopathogenic effect bacterial genetics bactericidal immunity biological signal transduction defensins enteric bacteria functional /structural genomics gastrointestinal epithelium gene expression genetic models genetically modified animals host organism interaction immunologic assay /test laboratory mouse laboratory rabbit model design /development peptide structure polymerase chain reaction recombinant DNA transfection /expression vector
项目摘要
DESCRIPTION (provided by applicant): The discovery of antimicrobial peptides in
insects, lower vertebrates and mammals has unveiled a previously unrecognized
component of animal host defense. Antimicrobial peptides are gene-encoded
antibiotics with activity against many classes of microbes. Defensins are the
predominant family of such peptides in mammals. Studies by our group and others
have discovered that defensin peptides are expressed by mammalian mucosal
epithelial cells, providing them with the capacity to participate in local host
defense. Although the intestinal epithelium is a surface in continual contact
with luminal contents variably laden with microbes, infection is uncommon. Our
underlying hypothesis is that in humans, the epithelial defensins HD5 and HD6
contribute to antimicrobial defense of the enteric mucosa. In this grant
proposal, we will test biological functions of epithelial antimicrobial
peptides in vivo through transgenic expression of HD5 and HD6 peptides in mice.
We propose that transgenic expression of these human defensins may provide mice
with an enhanced capacity to resist bacterial challenges. Based on preliminary
studies of our established transgenic mice, the experiments described here will
establish a clearer understanding of the contributions of human antimicrobial
peptides to innate host defense.
To test our hypotheses, Aim 1 will assay the immunological consequences of
human HD5 expression in transgenic mice. We will characterize the ability of
HD5 transgenic mice, compared to control wild-type mice, to resist enteric
infection by Salmonella typhimurium (Aim 1A), and parallel experiments will
extend to other enteric pathogens (Aim 1B). We will examine the impact of
transgenic HD5 expression on resident microflora of the mouse intestine (Aim
1C). The antimicrobial activity contributed by transgenic expression will be
quantitated in vitro, including analysis of isolated crypts (Aim 1D). The HD6
gene and peptide share little sequence identity to HD5, yet they are expressed
together in Paneth cells. In Aim 2, we will generate HD6 transgenic mice (Aim
2A) use recombinant HD6 to develop an antibody for immunoassays (Aim 2B), and
characterize the transgenic expression of HD6 at the gene and protein level
(Aim 2C). We will then characterize the effects of transgenic HD6 expression on
resistance to enteric bacterial colonization and infection (Aim 2D) using the
approaches developed in Aim 1. Finally, through lineage interbreeding we will
create HD5/HD6 compound transgenic mice to determine if these two peptides have
synergistic activities in vivo (Aim 2E). The proposed investigations, and other
studies of innate immunity, may provide insights yielding novel therapeutic
targets and approaches to combat infectious disease.
描述(由申请人提供):
昆虫、低等脊椎动物和哺乳动物揭示了一种以前未被认识的
动物宿主防御的组成部分。抗菌肽是基因编码的
对多种微生物有活性的抗生素。防御素是
哺乳动物中这类肽的主要家族。我们小组和其他人的研究
已经发现防御素肽由哺乳动物粘膜表达,
上皮细胞,使它们有能力参与当地宿主
防御虽然肠上皮是一个持续接触的表面,
由于管腔内容物充满微生物,感染是不常见的。我们
基本假设是,在人类中,上皮防御素HD5和HD6
有助于肠粘膜的抗微生物防御。在这份赠款中,
建议,我们将测试上皮抗菌剂的生物学功能,
通过在小鼠中转基因表达HD5和HD6肽在体内表达HD5和HD6肽。
我们认为这些人防御素的转基因表达可以为小鼠提供
具有增强的抵抗细菌挑战的能力。根据初步
我们建立的转基因小鼠的研究,这里描述的实验将
更清楚地了解人类抗菌素的贡献
肽对宿主先天防御的作用
为了验证我们的假设,目标1将分析
转基因小鼠中人HD5表达。我们将描述
HD5转基因小鼠,与对照野生型小鼠相比,抵抗肠
感染鼠伤寒沙门氏菌(目标1A),平行实验将
扩展到其他肠道病原体(目标1B)。我们将研究
转基因HD5在小鼠肠道常驻菌群上的表达(目的
1C)。转基因表达所贡献的抗微生物活性将是
体外定量,包括分离的隐窝分析(Aim 1D)。HD6
基因和肽与HD5共享很少的序列同一性,但它们表达
在Paneth细胞中。在目标2中,我们将产生HD6转基因小鼠(Aim
2A)使用重组HD6开发用于免疫测定的抗体(Aim 2B),和
在基因和蛋白水平上表征HD6的转基因表达
(Aim 2C)。然后,我们将表征转基因HD6表达对
对肠道细菌定植和感染的抗性(Aim 2D)
目标1中开发的方法。最后,通过血统杂交,
建立HD5/HD6复合转基因小鼠,以确定这两种肽是否具有
体内协同活性(Aim 2E)。拟议的调查和其他
先天免疫的研究,可能会提供新的治疗方法,
防治传染病的目标和方法。
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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Charles L Bevins其他文献
Rosacea: skin innate immunity gone awry?
酒渣鼻:皮肤先天免疫出错了吗?
- DOI:
10.1038/nm0807-904 - 发表时间:
2007-08-01 - 期刊:
- 影响因子:50.000
- 作者:
Charles L Bevins;Fu-Tong Liu - 通讯作者:
Fu-Tong Liu
Insulin gene expression in chicken ontogeny: pancreatic, extrapancreatic, and prepancreatic.
鸡个体发育中的胰岛素基因表达:胰腺、胰腺外和胰腺前。
- DOI:
10.1016/0012-1606(89)90237-6 - 发表时间:
1989 - 期刊:
- 影响因子:2.7
- 作者:
Jose Serrano;Charles L Bevins;Scott W. Young;F. Pablo - 通讯作者:
F. Pablo
Paneth cells: targets of friendly fire
帕内特细胞:误伤的目标
- DOI:
10.1038/ni.2519 - 发表时间:
2013-01-18 - 期刊:
- 影响因子:27.600
- 作者:
Stephen J McSorley;Charles L Bevins - 通讯作者:
Charles L Bevins
Antimicrobial Peptides as Mediators of Epithelial Host Defense
抗菌肽作为上皮宿主防御的介质
- DOI:
10.1203/00006450-199906000-00001 - 发表时间:
1999-06-01 - 期刊:
- 影响因子:3.100
- 作者:
Kenneth M Huttner;Charles L Bevins - 通讯作者:
Charles L Bevins
A sweet target for innate immunity
先天免疫的甜蜜靶标
- DOI:
10.1038/nm0310-263 - 发表时间:
2010-03-01 - 期刊:
- 影响因子:50.000
- 作者:
Fu-Tong Liu;Charles L Bevins - 通讯作者:
Charles L Bevins
Charles L Bevins的其他文献
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{{ truncateString('Charles L Bevins', 18)}}的其他基金
Paneth Cell Secreted Effectors in Mucosal Innate Immunity
粘膜先天免疫中的潘氏细胞分泌效应器
- 批准号:
9295954 - 财政年份:2016
- 资助金额:
$ 3.05万 - 项目类别:
2015 Antimicrobial Peptides Gordon Research Conference & Gordon Research Seminar
2015抗菌肽戈登研究会议
- 批准号:
8895489 - 财政年份:2015
- 资助金额:
$ 3.05万 - 项目类别:
New Mouse Models of Paneth Cell Defensin Function
潘氏细胞防御素功能的新小鼠模型
- 批准号:
8422985 - 财政年份:2012
- 资助金额:
$ 3.05万 - 项目类别:
New Mouse Models of Paneth Cell Defensin Function
潘氏细胞防御素功能的新小鼠模型
- 批准号:
8286104 - 财政年份:2012
- 资助金额:
$ 3.05万 - 项目类别:
Defensin gene copy number and mucosal innate immunity
防御素基因拷贝数和粘膜先天免疫
- 批准号:
7819960 - 财政年份:2010
- 资助金额:
$ 3.05万 - 项目类别:
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