PATHOGENESIS OF CELIAC DISEASE
乳糜泻的发病机制
基本信息
- 批准号:5210545
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:T cell receptor T lymphocyte celiac disease cell population study fusion gene gene expression genetic polymorphism genetically modified animals high performance liquid chromatography human subject laboratory mouse major histocompatibility complex mass spectrometry molecular pathology nucleic acid sequence pathologic process plant proteins protein sequence tissue /cell culture
项目摘要
Celiac disease is characterized by small intestinal mucosal injury and
the malabsorption of most nutrients. Disease is activated by the dietary
ingestion of wheat gliadin and similar alcohol soluble proteins in other
grains. Disease susceptibility is associated with a specific HLA class
II molecule (i.e., a DQw2 heterodimer) that is encoded by the DQA1*0501
and DQB1*0201 alleles. T cells play an important role in the activation
nd perpetuation of disease. Differences in the level of expression of
the disease associated DQ molecule relative to other HLA class II D
region molecules, or differences in its pattern of tissue specific
expression during ontogeny may be a critical factor in determining
disease susceptibility. We have defined polymorphisms in the 5'
regulatory region of the celiac disease associated DQA1*0501 allele
relative to other DQA1 alleles. Using chimeric reporter gene constructs
and DQA1*0501 transgenic mice, the first Aim of these studies will test
the hypothesis that these polymorphisms determine the level of expression
of DQA1*0501 relative to other DQA1 alleles or its tissue specific
pattern of expression during ontogeny. The specific peptide(s) of
gliadin that activate disease have not been precisely defined.
Therefore, a second Aim of these studies is to identify the endogenously
processed peptides of gliadin that are ligands for the human HLA DQw2
heterodimer associated with celiac disease. These experiments will
isolate DQw2 molecules that contain endogenously processed gliadin from
transfected cell lines that express only the DQw2 molecule and, in
collaboration, determine the amino acid sequence of those peptides by
HPLC and mass spectroscopy. The third Aim of these studies is to
characterize the specific T cell populations in celiac disease patients
that are important in the pathogenesis of this disease. These studies
will use a combination of molecular approaches a) to define the
alpha/beta and gamma/delta V genes used by T cell receptors that are
present in the celiac disease lesion of patients in remission and
patients with active disease, and to define the repertoire and clonality
of these receptors; b) to define the T cell receptors that recognize the
DQw2-gliadin peptide complex defined in Aim 2; and c) to characterize the
T cell receptors that are important in disease pathogenesis in the early
period after the activation of disease by in vivo challenge with gliadin
peptides. New information derived from these studies will help to define
the specific mechanisms by which specific HLA genes, gliadin peptides and
T cells contribute to the pathogenesis of celiac disease, and point to
new strategies for the prevention and treatment of this disease.
乳糜泻的特征是小肠粘膜损伤,
大多数营养素的吸收不良。 疾病是由饮食激活的
小麦麦醇溶蛋白和类似醇溶性蛋白的摄入
晶粒 疾病易感性与特定的HLA类相关
II分子(即,DQw 2异二聚体),其由DQA 1 *0501编码
和DQB 1 *0201等位基因。 T细胞在活化中起重要作用
和疾病的延续。 表达水平的差异
相对于其它HLA II D类的疾病相关DQ分子
区域分子,或其组织特异性
个体发育过程中的表达可能是决定
疾病易感性 我们已经定义了5'端的多态性,
乳糜泻相关DQA 1 *0501等位基因调控区
相对于其他DQA 1等位基因。 使用嵌合报告基因构建体
和DQA 1 *0501转基因小鼠,这些研究的第一个目的将测试
假设这些多态性决定表达水平,
DQA 1 *0501相对于其他DQA 1等位基因或其组织特异性
个体发育过程中的表达模式。 的特异性肽,
激活疾病麦醇溶蛋白尚未被精确定义。
因此,这些研究的第二个目的是识别内源性的
作为人HLA DQw 2配体的麦醇溶蛋白的加工肽
与乳糜泻相关的异源二聚体 这些实验将
分离含有内源加工麦醇溶蛋白的DQw 2分子,
仅表达DQw 2分子的转染细胞系,
合作,确定这些肽的氨基酸序列,
HPLC和质谱。 这些研究的第三个目的是
描述乳糜泻患者的特异性T细胞群
在这种疾病的发病机制中很重要。 这些研究
将使用分子方法的组合a)来定义
T细胞受体所使用的α/β和γ/δ V基因,
存在于缓解期患者的乳糜泻病变中,
活动性疾病的患者,并定义库和克隆性
B)定义识别这些受体的T细胞受体,
目的2中定义的DQw 2-麦醇溶蛋白肽复合物;以及
T细胞受体在疾病的早期发病机制中是重要的,
用麦醇溶蛋白体内激发疾病后的时间
缩氨酸 从这些研究中获得的新信息将有助于确定
特定的HLA基因、麦胶蛋白肽和
T细胞有助于乳糜泻的发病机制,并指出,
预防和治疗这种疾病的新策略。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('MARTIN F KAGNOFF', 18)}}的其他基金
INTESTINAL IMMUNE FUNCTION IN HOMOSEXUAL MALES WITH/WITHOUT AIDS
患有/未患有艾滋病的同性恋男性的肠道免疫功能
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4703644 - 财政年份:
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