GENE DEFECTIVE IN HEREDITARY HEMOCHROMATOSIS

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，铁吸收增加会导致铁中毒 在各种器官中沉积，导致肝硬变，肝细胞癌， 糖尿病、心力衰竭、关节炎和阳萎。一个MHC类的I类 候选基因，称为人类白细胞抗原-H，已经被发现。近90%的HH 患者是同一突变(C282Y)或复合突变的纯合子 人类白细胞抗原-H基因C282Y和H63D突变杂合子其他研究也有 也间接地与铁代谢中的MHC类I类蛋白有关，但 铁吸收的实际机制以及人类白细胞抗原-H是如何调节它的是 未知。 这项研究的主要目标是了解人类白细胞抗原-H的功能 并检验该基因中C282Y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(S)对人类白细胞抗原H基因性质的影响 表达产物在COS细胞中表达。2)纯化正常和突变 并鉴定其配体(S)和其他相互作用的蛋白。 3)用免疫组织化学方法研究HH基因突变对血管内皮细胞生长的影响(S) 人类白细胞抗原-H蛋白在小鼠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 已知的老鼠突变会增加铁的吸收，在 人类白细胞抗原-H基因产物在小鼠体内的表达和定位。5) 通过靶向基因干扰建立HH基因敲除小鼠模型 人类白细胞抗原H基因。各种生化、分子、细胞生物学和 免疫学技术将被用于这些研究，这些研究还包括 现代小鼠遗传学的优势。预计会有一个角色， 人类白细胞抗原-H基因产物在铁稳态调节中的作用将被确立 以及两人描述这种蛋白质突变的机制 对HH的贡献将被定义。这些研究不仅将改善我们的 了解铁吸收是如何正常调节的，但也可能 提出治疗铁过度吸收障碍的新策略。

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.