GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS
GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS
批准号:
6164558
负责人:
WILLIAM S SLY
金额:
$25.44万
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
项目状态:
已结题
起止时间:
1998-05-11 至 2003-02-28
关键词:
MHC class I antigen cell line clinical research dietary iron endoscopy gastrointestinal nutrient absorption gene mutation gene targeting genetically modified animals hereditary hemochromatosis human subject human tissue immunocytochemistry iron metabolism laboratory mouse laboratory rabbit major histocompatibility complex molecular pathology nutrition related tag protein localization
中文摘要
描述:遗传性血色病(HH)是一种非常常见的常染色体
一种隐性疾病,其中铁吸收增加导致铁中毒
沉积在各种器官中,导致肝硬化,肝细胞癌,
糖尿病心力衰竭关节炎和阳痿 一种MHC I类分子
一个叫做HLA-H的候选基因已经被确认。 近90%的HH
患者是相同突变(C282 Y)的纯合子,或复合突变
HLA-H中C282 Y和H63 D突变的杂合子。 其他研究
也间接牵连MHC I类蛋白在铁代谢,但
铁吸收的实际机制以及HLA-H如何调节铁吸收,
未知
这项研究的主要目标是了解HLA-H的功能,
基因产物,并测试该基因中的C282 Y突变的假设,
是HH的分子基础。 五个具体目标是:1)表征
HH突变对HLA-H基因特性的影响
在转染的COS细胞中表达产物。 2)纯化正常和突变体
HLA-H蛋白并鉴定其配体和其他相互作用蛋白。
3)使用免疫组织化学证明HH突变对
HLA-H蛋白在组织中的细胞和亚细胞定位
HH患者。 4)确定铁负荷的影响,以及
已知增加铁吸收的小鼠突变,
HLA-H基因产物在小鼠中的表达和定位。 第五章)
通过靶向基因破坏HH基因产生HH敲除小鼠模型。
HLA-H基因 各种生物化学、分子、细胞生物学和
这些研究将采用免疫学技术,
现代小鼠遗传学的优势。 预计,
HLA-H基因产物在铁稳态调节中的作用将得以确立
以及这两种蛋白质突变的机制
对HH的贡献将被定义。 这些研究不仅可以改善我们的
了解铁的吸收是如何正常调节的,但也可能
提出了治疗铁吸收过度紊乱的新策略。
英文摘要
DESCRIPTION: Hereditary hemochromatosis (HH) is a very common autosomal
recessive disorder in which increased iron absorption leads to toxic iron
deposits in a variety of organs causing cirrhosis, hepatocellular cancer,
diabetes, heart failure, arthritis, and impotence. An MHC class I-like
candidate gene, called HLA-H, has been identified. Nearly 90% of HH
patients are homozygous for the same mutation (C282Y), or compound
heterozygotes for C282Y and H63D mutations in HLA-H. Other studies have
also indirectly implicated MHC class I-like proteins in iron metabolism, but
the actual mechanism of iron absorption and how HLA-H could regulate it are
unknown.
The broad goals of this research are to understand the function of the HLA-H
gene product and to test the hypothesis that the C282Y mutation in this gene
is the molecular basis for HH. The five specific aims are: 1) Characterize
the effects of the HH mutation(s) on the properties of the HLA-H gene
product expressed in transfected COS cells. 2) Purify normal and mutant
HLA-H proteins and identify their ligand(s) and other interacting proteins.
3) Use immunohistochemistry to demonstrate the effects of HH mutations(s) on
the cellular and subcellular localization of the HLA-H protein in tissues of
HH patients. 4) Determine the effects of iron loading, and the effects of
mouse mutations known to increase iron absorption, on the level of
expression and the localization of the HLA-H gene product in mice. 5)
Produce a knockout mouse model for HH by targeted gene disruption of the
HLA-H gene. A variety of biochemical, molecular, cell biological, and
immunological techniques will be employed for these studies which also take
advantage of modern mouse genetics. It is expected that a role for the
HLA-H gene product in the regulation of iron homeostasis will be established
and the mechanisms by which the two described mutations in this protein
contribute to HH will be defined. These studies will not only improve our
understanding of how iron absorption is normally regulated, but may also
suggest new strategies for treating disorders of excessive iron absorption.
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GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS
-
批准号:6517440
-
项目类别:
-
资助金额:$26.9万
-
财政年份:1998
-
负责人:WILLIAM S SLY
-
依托单位:
GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS
-
批准号:2452428
-
项目类别:
-
资助金额:$26.06万
-
财政年份:1998
-
负责人:WILLIAM S SLY
-
依托单位:
GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS
-
批准号:6363007
-
项目类别:
-
资助金额:$26.18万
-
财政年份:1998
-
负责人:WILLIAM S SLY
-
依托单位:
GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS
-
批准号:2882807
-
项目类别:
-
资助金额:$26.87万
-
财政年份:1998
-
负责人:WILLIAM S SLY
-
依托单位:
Receptor-mediated transport of lysosomal enzymes
-
批准号:8446506
-
项目类别:
-
资助金额:$35.23万
-
财政年份:1995
-
负责人:WILLIAM S SLY
-
依托单位:
Receptor-mediated transport of lysosomal enzymes
-
批准号:7889723
-
项目类别:
-
资助金额:$36.88万
-
财政年份:1995
-
负责人:WILLIAM S SLY
-
依托单位:
Receptor-mediated transport of lysosomal enzymes
-
批准号:8245761
-
项目类别:
-
资助金额:$36.51万
-
财政年份:1995
-
负责人:WILLIAM S SLY
-
依托单位:
Receptor-mediated transport of lysosomal enzymes
-
批准号:8055281
-
项目类别:
-
资助金额:$36.51万
-
财政年份:1995
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:6476162
-
项目类别:
-
资助金额:$43.49万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:2141206
-
项目类别:
-
资助金额:$31.45万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:6624857
-
项目类别:
-
资助金额:$44.58万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:2141204
-
项目类别:
-
资助金额:$29.08万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:3240266
-
项目类别:
-
资助金额:$27.77万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:2444013
-
项目类别:
-
资助金额:$32.71万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:3240267
-
项目类别:
-
资助金额:$24.52万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
Biochemical Genetics of Carbonic Anhydrase Deficiencies
-
批准号:7027122
-
项目类别:
-
资助金额:$51.67万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
Biochemical Genetics of Carbonic Anhydrase Deficiencies
-
批准号:7194965
-
项目类别:
-
资助金额:$51.67万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:2141205
-
项目类别:
-
资助金额:$30.24万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
Biochemical Genetics of Carbonic Anhydrase Deficiencies
-
批准号:6776733
-
项目类别:
-
资助金额:$49.87万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
BIOCHEMICAL GENETICS OF CARBONIC ANHYDRASE DEFICIENCIES
-
批准号:3240268
-
项目类别:
-
资助金额:$25.25万
-
财政年份:1988
-
负责人:WILLIAM S SLY
-
依托单位:
海外基金