IRON

铁

• 批准号: 7607599
• 负责人: Petr Protiva
• 金额: $ 1.21万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7607599
• 关键词: Age; Angiotensinogen; Apolipoprotein E; Asorbicap; Blood Vessels; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Clinical Data; Computer Retrieval of Information on Scientific Projects Database; Coupled; Disease; Disease Outcome; End Point; Ethnic Origin; Frequencies; Funding; Gene Expression; Gene Mutation; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; HLA Antigens; Hepatic; Hepatitis C; Hereditary hemochromatosis; Human Genome Project; Institution; Integration Host Factors; Interferons; Interleukins; Iron; Knowledge; Link; Medical; Microsomal Epoxide Hydrolase; Mutation; Outcome; Patients; Phenotype; Predisposition; Primary carcinoma of the liver cells; Production; Proteins; Proteomics; RNA; Research; Research Personnel; Resources; Role; Sampling; Severities; Severity of illness; Source; Transforming Growth Factor beta; Translating; Translations; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Variant; base; human disease; improved; neoplastic; next generation; programs; promoter; response; sex; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The success of the human genome project provides the promise of a new era in understanding and modifying human disease. It seems both likely and feasible that, during the next generation, we will identify the major host genes and their genetic variations, which modulate susceptibility to and severity of disease and responsiveness to medical therapies. To translate this promise into reality will require careful clinical characterizations of different patient phenotypes, coupled with determination of genotypes (genetic variations), gene expression information Messenger Ribonucleic Acid (mRNA's by microarrays, etc.), and information about translation of mRNA's into proteins (proteomics). A few studies have already identified genotypes that predict with greatly improved accuracy susceptibility to chronic vascular or neoplastic diseases and/or severity and outcome of these diseases. This project will take full advantage of the samples and clinical data obtained through the landmark HALT-C Trial, in order to develop a similar body of knowledge for chronic hepatitis C (CHC). The long-term goal of this program is to ascertain the major genetic variations that predispose patients to develop advanced CHC and/or lack of responsiveness to (Interferon) IFN-based treatment. We will concentrate our efforts on variations in selected genes, which in previous smaller studies, have been shown to predict severity of CHC and/or responsiveness to IFN treatment. Specifically, we will delineate the role of iron, HFE gene mutations, and/or polymorphisms in other selected genes or gene promoters on the production and progression of CHC. Our major hypotheses are that hepatic iron, mutations of the HFE gene associated with human leukocyte antigen (HLA)-linked hereditary hemochromatosis (HHC), and/or selected polymorphisms in other genes, are important host factors that influence the progression of chronic hepatitis C to cirrhosis, decompensation, and hepatocellular carcinoma and/or the response of CHC to IFN-based therapies. The specific aims of this project are: To determine whether there is a direct correlation between progression of chronic hepatitis C (i.e., the major endpoints of the HALT-C Trial) and hepatic or total body iron content and/or the presence of the HFE gene mutations (C282Y, H63D, S65C) associated with HHC; To determine whether there are correlations between progression of chronic hepatitis C and polymorphisms of the angiotensinogen promoter (Ang-P), apolipoprotein E (apo-E) genotype, the interleukin-I0 promoter (IL-10-P), microsomal epoxide hydrolase (mEH), transforming growth factor-beta (TGF), or the tumor necrosis factor-alpha promoter (TNF-P); To explore whether there are significant interactions among mutations of HFE, polymorphisms of other genes, and patients' responses to therapy or long-term outcomes; and To determine whether the frequencies of these genetic variations differ significantly among subjects in the HALT-C Trial vs other subjects with less advanced CHC, or control subjects without CHC, matched for age, sex, and ethnicity.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 人类基因组项目的成功为理解和改变人类疾病的新时代提供了希望。 在下一代中，我们将确定主要的宿主基因及其遗传变异，从而调节疾病的易感性和严重性以及对医疗疗法的反应能力，似乎既可能又可行。 将这一诺言转化为现实，将需要对不同患者表型进行仔细的临床特征，并确定基因型（遗传变异），基因表达信息信息信使核糖核酸（MRNA's by Microarrays等）以及有关mRNA转化为蛋白质（蛋白质组）的信息。 一些研究已经确定了基因型，这些基因型可以大大提高对慢性血管或肿瘤疾病的准确性敏感性和/或这些疾病的严重性以及这些疾病的结果。 该项目将充分利用通过Landmark Halt-C试验获得的样品和临床数据，以开发类似的慢性乙型肝炎（CHC）知识体系。 该计划的长期目标是确定使患者易于发展晚期CHC和/或对基于IFN的治疗的反应性的主要遗传变异。 我们将精力集中在选定基因的变化上，在先前的较小研究中，已被证明可以预测CHC的严重程度和/或对IFN治疗的反应性。 具体而言，我们将描述铁，HFE基因突变和/或多态性在其他选定基因或基因启动子中对CHC的产生和进展中的作用。 Our major hypotheses are that hepatic iron, mutations of the HFE gene associated with human leukocyte antigen (HLA)-linked hereditary hemochromatosis (HHC), and/or selected polymorphisms in other genes, are important host factors that influence the progression of chronic hepatitis C to cirrhosis, decompensation, and hepatocellular carcinoma and/or the response of CHC基于IFN的疗法。 该项目的具体目的是： 确定慢性丙型肝炎的进展（即HALT-C试验的主要终点）与HFE基因突变（C282Y，H63D，S65C）的存在之间是否存在直接相关性； 确定慢性丙型肝炎的进展与血管紧张素原成蛋白（ANG-P），载脂蛋白E（APO-E）基因型的进展与多态性之间存在相关性（TNF-P）; 探索HFE突变，其他基因的多态性以及患者对治疗或长期结局的反应之间是否存在显着相互作用；和 确定在HALT-C试验中与其他CHC较低的受试者或没有CHC的对照受试者的受试者中，这些遗传变异的频率是否有显着差异，与年龄，性别和种族相匹配。