HFE: A Genetic Determinant of Olfactory Mn Absorption and Toxicity

HFE：嗅觉锰吸收和毒性的遗传决定因素

• 批准号: 7713292
• 负责人: Marianne Wessling-Resnick
• 金额: $ 16.35万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7713292
• 关键词: Adult; Alleles; American; Animals; Behavior; Brain; Brain region; Breathing; Bypass; Deposition; Diet; Drug Kinetics; Exposure to; Genes; Genetic Determinism; Hemochromatosis; Hereditary Disease; Hereditary hemochromatosis; Intestinal Absorption; Intestines; Iron; Knockout Mice; Laboratories; Liver Circulation; Manganese; Measures; Metabolism; Metals; Modeling; Motor; Mus; Neuraxis; Neurologic; Neurotoxins; Olfactory Epithelium; Olfactory Pathways; Pathway interactions; Pilot Projects; Play; Population; Predisposition; Prevalence; Role; SLC11A2 gene; Smell Perception; System; Testing; Time; Tissues; Toxic effect; Up-Regulation; Variant; Work; absorption; caucasian American; divalent metal; genetic variant; mouse model; olfactory bulb; public health relevance

DESCRIPTION (provided by applicant): Genetic variants of the HFE gene are the leading cause of adult onset hereditary hemochromatosis (HH), the most common Mendelian genetic disease in the North American Caucasian population. The missense variants C282Y and H63D promote increased intestinal absorption and progressive tissue deposition of iron. HH has also been associated with derangements in the metabolism of other divalent metals, and it is thought these effects arise due to malregulation of divalent metal transporter (DMT1). Work in our laboratory has demonstrated that manganese can enter the central nervous system directly across the olfactory epithelium by a mechanism that involves DMT1. We therefore hypothesize that carriers of C282Y and/or H63D HFE alleles may be more susceptible to manganese exposure through the olfactory pathway, and consequently may have impaired olfactory function. Our model further suggests that Hfe-/- knockout mice would have increased 54Mn absorption through the olfactory system and that these animals would be more sensitive to manganese exposures causing impaired olfaction. This pilot project will test the hypothesis that HFE acts as a genetic determinant of olfactory manganese absorption and toxicity. PUBLIC HEALTH RELEVANCE: Genetic variants of the HFE gene are the leading cause of adult onset hereditary hemochromatosis (HH), the most common Mendelian genetic disease in the North American Caucasian population. The missense variants C282Y and H63D promote increased intestinal absorption and progressive tissue deposition of iron. Our hypothesis is that HFE acts as a genetic determinant of olfactory manganese absorption and toxicity. To test this hypothesis, we will study a mouse model of HFE-associated hemochromatosis to test whether absorption of inhaled manganese is altered, and whether HFE therefore promotes a greater susceptibility to damage to olfaction - the sense of smell.

描述（由申请人提供）：HFE基因的遗传变异是成人发作遗传性血色素沉着症（HH）的主要原因，这是北美高加索人群中最常见的孟德尔遗传疾病。错义变体C282Y和H63D促进了铁的肠道吸收和进行性组织沉积。 HH还与其他二价金属的代谢中的危险有关，并且认为这些效应是由于二价金属转运蛋白的破坏而产生的（DMT1）。我们实验室的工作表明，锰可以通过涉及DMT1的机制直接进入嗅觉上皮的中枢神经系统。因此，我们假设C282Y和/或H63D HFE等位基因的载体可能更容易通过嗅觉途径暴露，因此可能会损害嗅觉功能。我们的模型进一步表明，HFE - / - 基因敲除小鼠将通过嗅觉系统增加54MN的吸收，并且这些动物对锰暴露更敏感，从而导致嗅觉受损。该试点项目将检验以下假设：HFE充当嗅觉吸收和毒性的遗传决定因素。 公共卫生相关性：HFE基因的遗传变异是成人发作遗传性血色素沉着症（HH）的主要原因，这是北美高加索人群中最常见的门德尔遗传疾病。错义变体C282Y和H63D促进了铁的肠道吸收和进行性组织沉积。我们的假设是HFE充当嗅觉吸收和毒性的遗传决定因素。为了检验这一假设，我们将研究与HFE相关的血色素沉着症的小鼠模型，以测试吸入锰的吸收是否改变，因此HFE是否会促进对嗅觉损害的更大敏感性 - 气味感。