INDUCTION OF IG C EPSILON & C GAMMA 1 BY IL4 & CD40L
IG C Epsilon 感应
基本信息
- 批准号:6510760
- 负责人:
- 金额:$ 26.2万
- 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:1998-07-01 至 2003-05-31
- 项目状态:已结题
- 来源:
- 关键词:B lymphocyte CD40 molecule DNA binding protein DNA footprinting biological signal transduction chimeric proteins chromatin crosslink gene mutation gene rearrangement genetic promoter element immunoglobulin E immunoglobulin G immunoglobulin genes interleukin 4 laboratory mouse nuclear factor kappa beta nucleosomes polymerase chain reaction protein binding tissue /cell culture transcription factor transfection
项目摘要
After immunization or infection, B cells undergo immunoglobulin (Ig) class
switching, which results in expression of a new heavy chain constant
region (C/H) region gene. Class switching allows the humoral immune
response to adaptively respond to a variety of different infectious
organisms to produce the best antibody for each pathogen. This proposal
will investigate the mechanism of regulation of class switching to IgG1
and IgE, using the mouse a model system. This proposal will investigate
the mechanism of regulation of class switching to IgG1 and IgE, using the
mouse as a model system. Both IgG1 and IgE are produced in response to T
dependent antigens, although IgG1 in much greater abundance that IgE. IgG1
in effective against bacterial, viral and nematode infections due to its
ability to active complement and to bind to FcRgammaIII on macrophages,
neutrophils, mast cells and NK cells. IgE helps to eliminate parasitic
helminths, although it does not appear to be essential for this immune
response and in industrial societies is generally more dangerous than
protective, as it causes allergy, including asthma. Thus, the ability to
increase IgG1 and decrease IgE responses would be useful medically.
Numerous studies have established that transcription of the C/H gene to
which cells will switch is induced prior to switching by cytokines and B
cell activators, and that this transcription is required for class
switching. This proposal is to investigate the mechanism of regulation of
germline gamma1 and epsilon transcription by cytokines and B cell
activators known to regulate class switching to IgG1 and IgE. The proposal
will specifically investigate and compare the regulation of the germline
gamma1 and epsilon transcripts by three transcription factors/families
which are involved in induction of transcription by IL-4 and CD40
signaling: Stat6, NF-kappaB/Rel proteins, and b-Zip proteins. We have
shown that Stat6 and NF-kappaB directly bind each other and have evidence
suggesting this is the mechanism whereby IL-4 and CD40 signaling
synergistically induce transcription. This proposal will directly address
whether this binding is necessary for their synergy and analyze the
mechanism of their interaction. A b-Zip binding site which binds Ap-1 is
also required for the ability of Stat6 to induce transcription, but the
requirement for the Ap-1 binding site is not understood. We will
investigate whether this requirement is due to the inability of Stat6 to
bind to chromatin in vivo in the absence of AP-1. The promoters for the
gamma1 and epsilon germline transcripts have similar binding sites for
Stat6, NF-kappaB and AP-1 (or for C/EBP), but these sites are
differentially arranged. We will determine if it is the differential
arrangement and/or different binding proteins at the b-Zip element which
regulates their different responses to IL-4 and B cell activators.
免疫或感染后,B细胞经历免疫球蛋白(IG)类
转换,导致表达新的重链常数
区域(C/H)基因。类转换使得体液免疫
适应性地应对各种不同的传染病
生物体产生最好的抗体每一种病原体。这项建议
将研究类转换为IgG 1的调节机制
和IgE,使用小鼠模型系统。该提案将调查
调节IgG 1和IgE类别转换的机制,使用
以老鼠为模型。IgG 1和IgE都是响应T而产生的
依赖性抗原,尽管IgG 1的丰度比IgE大得多。IgG1
由于其具有抗细菌、病毒和线虫感染作用,
激活补体并结合巨噬细胞上的FcR γ III的能力,
嗜中性粒细胞、肥大细胞和NK细胞。IgE有助于消除寄生虫
蠕虫,虽然它似乎并不是这种免疫所必需的,
在工业社会中,一般来说,
保护,因为它会引起过敏,包括哮喘。因此,
增加IgG 1和降低IgE应答在医学上是有用的。
许多研究已经证实,C/H基因的转录,
在细胞因子和B的转换之前,
细胞激活剂,并且这种转录是类
切换本研究旨在探讨调节的机制,
细胞因子和B细胞对生殖系γ 1和γ 2转录的影响
已知调节IgG 1和IgE类别转换的激活剂。该提案
将专门研究和比较生殖系的调节,
三个转录因子/家族的γ 1和γ 2转录物
参与IL-4和CD 40的转录诱导
信号传导:Stat 6、NF-κ B/Rel蛋白和b-Zip蛋白。我们有
显示Stat 6和NF-κ B直接相互结合,并有证据表明
提示这是IL-4和CD 40信号传导的机制,
协同诱导转录。该提案将直接针对
这种结合是否对它们的协同作用是必要的,并分析
他们的互动机制。结合Ap-1的b-Zip结合位点是
也是Stat 6诱导转录的能力所必需的,但是
对Ap-1结合位点的要求尚不清楚。我们将
调查这一要求是否是由于Stat 6无法
在缺乏AP-1的情况下,在体内结合染色质。The Promoters for the
γ 1和γ 2生殖系转录物具有相似的结合位点,
Stat 6、NF-κ B和AP-1(或C/EBP),但这些位点是
不同的安排。我们将确定是否是差异
在b-Zip元件处的不同排列和/或不同的结合蛋白,
调节它们对IL-4和B细胞活化剂的不同应答。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Activation of the mouse Ig germline epsilon promoter by IL-4 is dependent on AP-1 transcription factors.
IL-4 对小鼠 Ig 种系 epsilon 启动子的激活依赖于 AP-1 转录因子。
- DOI:10.4049/jimmunol.166.1.411
- 发表时间:2001
- 期刊:
- 影响因子:0
- 作者:Shen,CH;Stavnezer,J
- 通讯作者:Stavnezer,J
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Janet M. Stavnezer其他文献
Janet M. Stavnezer的其他文献
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{{ truncateString('Janet M. Stavnezer', 18)}}的其他基金
Function of the AID C terminus in Ig class switching
AID C 末端在 Ig 类别转换中的功能
- 批准号:
8292343 - 财政年份:2012
- 资助金额:
$ 26.2万 - 项目类别:
Molecular Basis of Immunoglobulin Heavy Chain Switch
免疫球蛋白重链开关的分子基础
- 批准号:
8090512 - 财政年份:2010
- 资助金额:
$ 26.2万 - 项目类别:
c-myc DNA breaks and c-myc-IgH locus translocations: roles of AID and oxidation
c-myc DNA 断裂和 c-myc-IgH 基因座易位:AID 和氧化的作用
- 批准号:
7865093 - 财政年份:2010
- 资助金额:
$ 26.2万 - 项目类别:
c-myc DNA breaks and c-myc-IgH locus translocations: roles of AID and oxidation
c-myc DNA 断裂和 c-myc-IgH 基因座易位:AID 和氧化的作用
- 批准号:
8097530 - 财政年份:2010
- 资助金额:
$ 26.2万 - 项目类别:
Molecular Basis of Immunoglobulin Heavy Chain Switch
免疫球蛋白重链开关的分子基础
- 批准号:
7846563 - 财政年份:2009
- 资助金额:
$ 26.2万 - 项目类别:
Isotype specific regulation of lg class switching
LG 类别转换的同种型特异性调节
- 批准号:
7140383 - 财政年份:2005
- 资助金额:
$ 26.2万 - 项目类别:
Isotype specific regulation of lg class switching
LG 类别转换的同种型特异性调节
- 批准号:
6965565 - 财政年份:2005
- 资助金额:
$ 26.2万 - 项目类别: