Serum Biomarkers Associated With Phenotypic Expression of Hemochromatosis.

与血色素沉着病表型表达相关的血清生物标志物。

• 批准号: 8262598
• 负责人: KRIS KOWDLEY
• 金额: $ 12.8万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262598
• 关键词: 3' Untranslated Regions; Accounting; Adult; American; Amino Acids; Area; Binding; Biochemical; Biological Markers; Biology; Blood Circulation; Blood specimen; Cardiomyopathies; Caucasians; Caucasoid Race; Cells; Characteristics; Cirrhosis; Clinical; Cysteine; Data; Development; Diabetes Mellitus; Diagnostic; Dietary Iron; Disease; Down-Regulation; Early Diagnosis; Enrollment; Ethnic group; Family history of; Family member; Ferritin; Functional RNA; Gene Expression; Gene-Modified; Genes; Genetic; Goals; HBV Cirrhosis; Heart; Hemochromatosis; Hepatic; Hereditary Disease; Hereditary hemochromatosis; Heterozygote; Histologic; Homeostasis; Homozygote; Inherited; Iron; Iron Overload; Joints; Laboratories; Left; Life; Life Expectancy; Life Style; Liver; Liver Cirrhosis; Liver diseases; Measures; Membrane; Messenger RNA; MicroRNAs; Missense Mutation; Molecular Profiling; Mutation; Organ; Pancreas; Participant; Pathology; Patients; Penetrance; Population; Prevalence; Primary Health Care; Primary carcinoma of the liver cells; Publishing; RNA Degradation; Race; Recruitment Activity; Regulation; Regulator Genes; Resources; Risk; Rodent Model; Role; SLC11A2 gene; Sampling; Screening procedure; Serum; Severities; Severity of illness; Skin; Testing; Transferrin; Translations; Tyrosine; Variant; absorption; base; chronic liver disease; genetic variant; hepcidin; insight; interest; iron metabolism; liver biopsy; mouse model; novel; particle; peripheral blood; prognostic; therapeutic target; tool; translational study

DESCRIPTION (provided by applicant): Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by a progressive accumulation of hepatic iron and is one of the most common inherited diseases among Caucasians with an estimated prevalence of 1 in 250 and a heterozygote carrier rate of 8%¿10% in the white population. If left untreated irreversible organ damage, cardiomyopathy, diabetes mellitus, cirrhosis and hepatocellular carcinoma can occur in the 4th or 5th decade of life. Nearly all cases of hemochromatosis are due to a homozygous missense mutation in the HFE gene that changes amino acid residue 282 from a cysteine to a tyrosine (C282Y). However, there is only partial penetrance of this mutation and many C282Y homozygotes are asymptomatic. Full clinical penetrance, such as marked organ damage, is much less common and may depend on ethnic, environmental or genetic factors. The presence of one or more disease modifying genes has been postulated but has yet to be proven. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3' untranslated regions of messenger RNAs (mRNAs) to promote mRNA degradation and/or block translation. Recent studies have shown that levels of many circulating serum miRNA are elevated in patients with a variety of liver diseases and pathologies including HCC, HBV and liver cirrhosis, therefore serum miRNAs represent a new type of diagnostic and prognostic biomarker, and potential therapeutic target for several liver diseases. The role of miRNAs in HH is uncharacterized, although a liver specific miRNA miR-122 was recently shown to be involved in mammalian iron homeostasis by repressing the expression of hepcidin and its activators, the Hfe and Hjv genes in a mouse model of hemochromatosis. We are proposing a multifaceted approach to identify novel serum biomarkers, serum hepcidin levels and miRNA gene expression profiles that underlie potential iron homeostasis regulatory mechanisms. The proposed studies are feasible, will harness the vast resources of the HEIRS Study and will provide a unique opportunity to determine novel mechanisms involved in the penetrance of the C282Y HFE mutation.

描述（由申请人提供）：遗传性血色素症（HH）是一种常染色体隐性疾病，其特征是肝铁的进行性积累，是高加索人中最常见的遗传性疾病之一，估计患病率为250，是杂合子载体载体速率的患病率。 8％在白人人群中，如果不可逆的器官损害，则可以在第四或第五个生命中发生心脏疾病。酪氨酸（C282Y）是无症状的。 ）是小的非编码RNA，通过与3'未翻译的Messenger RNA（mRNA）中的部分置换靶序列对基因表达进行负调节，以促进mRNA降解和/或阻滞Y循环平移。各种肝病和病理学，包括HCC，HBV和肝脏肝硬化，因此血清miRNA代表了一种新型的诊断和程序仪表式生物标志物，miRNA在HH中的作用是未经表达的。通过肝素及其活化剂的表达稳态，在血色素型小鼠模型中，HFE和HJV基因都可以识别为IRUM生物标志物，血清肝素水平和miRNA基因表达了潜在的铁SIS调节机制支撑研究是可行的，继承人研究的庞大资源将为C282Y HFE突变的渗透率提供独特的机会阿坦（Isms）的独特机会。