CYTOKINE MECHANISMS IN SYSTEMIC AUTOIMMUNITY
系统性自身免疫中的细胞因子机制
基本信息
- 批准号:6226991
- 负责人:
- 金额:$ 28.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-09-30 至 2003-09-29
- 项目状态:已结题
- 来源:
- 关键词:B lymphocyte antibody formation autoantibody cytokine disease /disorder model gene mutation genetically modified animals interferon gamma interleukin 12 interleukin 4 laboratory mouse leukocyte activation /transformation natural killer cells pathologic process systemic lupus erythematosus transcription factor
项目摘要
DESCRIPTION: (Adapted from applicant's abstract) The Th1/Th2 cytokine balance
is believed to be a prominent factor in determining susceptibility, progression
and prognosis in autoimmune diseases. It remains unclear which subset of Th
cells play a more critical role in systemic autoimmune diseases such as SLE.
Inconclusive results obtained so far suggest that both Th1 and Th2-type
cytokines may be involved, and that the regulatory roles of such cytokines are
very complex. The hypothesis we would like to explore in the present
application is that the systemic autoimmune disease SLE is a multistage disease
process in which Th1 and Th2 cytokines effect different aspects and different
stages of disease development. We propose a genetic approach to study the
mechanisms of autoimmune disease development employing a novel set of
genetically manipulated mice. Signal transducers and activators of
transcription (STAT) proteins are a class of transcription factors responsible
for mediating many cytokine-induced responses. Recently, several groups have
produced mice that lack one or the other Stat gene. The Stat-4 knockout mice
are deficient in IL-12 functions including IFNg induction and Th1
differentiation. The Stat-6 knockout mice, on the other hand, are deficient in
IL4 induced functions including Th2 differentiation. We have genetically
transferred Stat-4 and Stat-6 null mutations onto the lupus susceptibility
background of (NZBXNZW)Fl which is arguably the best available animal model for
SLE. For this purpose two New Zealand Mixed congenic strains, NZM2410 and
NZM2328, were used and four novel knockout mouse lines were created, the
Stat4-/-. NZM2410, the Stat6-/-.NZM2410, the Stat4-/-.NZM2328 and the
Stat6-/-.NZM2328, employing a marker-assisted selection protocol (MASP)
strategy to accelerate and control the development of the desired congenic mice
strains. In the proposed studies, we intend to characterize the development and
progression of autoimmune disease in these four genetically manipulated new
mouse lines, and to evaluate immune regulatory mechanisms pertinent to the
development of autoimmunity. This application integrates the talents of a
multidiscipline team combining expertise in genetics and cytokine biological
aspects of autoimmune disease development (Dr. Jacob's group) with expertise in
the B cell immunology and autoantibodies (Dr. Reeves' group) and T and NK cell
immunobiology (Dr. Dennert's group).
描述:(改编自申请人摘要)Th 1/Th 2细胞因子平衡
被认为是决定易感性、进展
和自身免疫性疾病的预后。目前尚不清楚Th
细胞在系统性自身免疫性疾病(例如系统性红斑狼疮)中发挥着更关键的作用。
迄今为止获得的非决定性结果表明,Th 1和Th 2型
可能涉及细胞因子,并且这些细胞因子的调节作用是
非常复杂。我们现在想探讨的假设是
系统性自身免疫性疾病SLE是一种多阶段疾病,
Th 1和Th 2细胞因子影响不同方面和不同的过程
疾病发展的各个阶段。我们提出了一种遗传学方法来研究
自身免疫性疾病发展的机制,采用一套新的
基因操控的老鼠信号转导和激活因子
转录(STAT)蛋白是一类负责
用于介导许多尼古丁诱导的反应。最近,几个团体
产生了缺少一种或另一种Stat基因的小鼠。Stat-4基因敲除小鼠
缺乏IL-12功能,包括IFNg诱导和Th 1
分化另一方面,Stat-6基因敲除小鼠缺乏
IL 4诱导的功能包括Th 2分化。从基因上来说
将Stat-4和Stat-6无效突变转移到狼疮易感性上
(NZBXNZW)Fl的背景,其可以说是用于治疗糖尿病的最佳可用动物模型。
SLE。为此目的,两种新西兰混合同源菌株NZM 2410和
NZM 2328,并建立了四个新的敲除小鼠系,
Stat4-/-。NZM 2410、Stat 6-/-.NZM2410、Stat 4-/-.NZM2328和
Stat 6-/-.NZM2328,采用标记辅助选择方案(MASP)
加速和控制所需同类小鼠发育的策略
菌株在拟议的研究中,我们打算描述其发展特征,
在这四个基因操作的新的自身免疫性疾病的进展
小鼠系,并评估与免疫调节机制有关的,
自身免疫的发展。这个应用程序集成了一个
结合遗传学和细胞因子生物学专业知识的多学科团队
自身免疫性疾病发展的各个方面(雅各布博士的小组),
B细胞免疫学和自身抗体(Reeves博士小组)以及T和NK细胞
免疫生物学(Dennert博士的小组)。
项目成果
期刊论文数量(1)
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('CHAIM O. JACOB', 18)}}的其他基金
Leukocyte NADPH Oxidase Variants in Lupus
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9993339 - 财政年份:2017
- 资助金额:
$ 28.44万 - 项目类别:
Leukocyte NADPH Oxidase Variants in Lupus
狼疮中的白细胞 NADPH 氧化酶变异体
- 批准号:
10396966 - 财政年份:2017
- 资助金额:
$ 28.44万 - 项目类别:
Leukocyte NADPH Oxidase Variants in Lupus
狼疮中的白细胞 NADPH 氧化酶变异体
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Elucidation of novel gene variants predisposing to childhood and adult-onset SLE
阐明易患儿童和成人 SLE 的新基因变异
- 批准号:
8225331 - 财政年份:2010
- 资助金额:
$ 28.44万 - 项目类别:
Elucidation of novel gene variants predisposing to childhood and adult-onset SLE
阐明易患儿童和成人 SLE 的新基因变异
- 批准号:
8425063 - 财政年份:2010
- 资助金额:
$ 28.44万 - 项目类别:
Elucidation of novel gene variants predisposing to childhood and adult-onset SLE
阐明易患儿童和成人 SLE 的新基因变异
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8602511 - 财政年份:2010
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Elucidation of novel gene variants predisposing to childhood and adult-onset SLE
阐明易患儿童和成人 SLE 的新基因变异
- 批准号:
7783739 - 财政年份:2010
- 资助金额:
$ 28.44万 - 项目类别:
Elucidation of novel gene variants predisposing to childhood and adult-onset SLE
阐明易患儿童和成人 SLE 的新基因变异
- 批准号:
8034252 - 财政年份:2010
- 资助金额:
$ 28.44万 - 项目类别:
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7434329 - 财政年份:2004
- 资助金额:
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