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病遗传性血色病（HH）的主要原因，HH是北美高加索人群中最常见的孟德尔遗传病。错义变体C282 Y和H63 D促进铁的肠吸收增加和进行性组织沉积。HH还与其他二价金属代谢紊乱有关，并且认为这些影响是由于二价金属转运蛋白（DMT 1）的失调引起的。我们实验室的工作表明，锰可以通过涉及DMT 1的机制直接穿过嗅上皮进入中枢神经系统。因此，我们假设C282 Y和/或H63 D HFE等位基因的携带者可能更容易通过嗅觉途径暴露于锰，因此可能具有受损的嗅觉功能。我们的模型进一步表明，Hfe-/-敲除小鼠将通过嗅觉系统增加54 Mn吸收，并且这些动物将对锰暴露更敏感，从而导致嗅觉受损。该试点项目将测试HFE作为嗅觉锰吸收和毒性的遗传决定因素的假设。 公共卫生相关性：HFE基因的遗传变异是成人发病遗传性血色病（HH）的主要原因，HH是北美高加索人群中最常见的孟德尔遗传病。错义变体C282 Y和H63 D促进铁的肠吸收增加和进行性组织沉积。我们的假设是，HFE作为嗅觉锰吸收和毒性的遗传决定因素。为了验证这一假设，我们将研究HFE相关血色素沉着症的小鼠模型，以测试吸入锰的吸收是否改变，以及HFE是否因此促进对嗅觉（嗅觉）损伤的更大易感性。