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Copper Homeostasis in Mammals

哺乳动物的铜稳态

基本信息

批准号：
9317601
负责人：
Dennis J Thiele
金额：
$ 43.48万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317601
关键词：
Affinity African American Anemia Animal Model Area Automobile Driving B-Lymphocytes Binding Biochemical Biochemical Reaction Cardiac Cardiac Catheterization Procedures Cardiac health Cardiomegaly Cardiomyopathies Cathepsin L Cathepsins Cathepsins B Cell Culture Techniques Cells Cessation of life Clinic Cognitive Cognitive deficits Copper Data Defect Deficiency Diseases Diet Disease Embryonic Development Enzymes Epithelial Event Genes Genetic Polymorphism Growth Health Heart Diseases Heart failure Homeostasis Hospitals Human Hypertrophic Cardiomyopathy Impairment In Vitro Integral Membrane Protein Intestines Iron Lead Length Life Link Mammalian Cell Mammals Measurement Measures Mediating Membrane Metabolism Mus Mutation Myocardial dysfunction Myocardium Nature Neurologic Neutropenia Patients Peptide Hydrolases Peripheral Peripheral Nervous System Diseases Physiological Play Process Proteins Proteolysis Publishing Regulation Research Role Serum Single Nucleotide Polymorphism Testing Tissues Trace Elements Trace metal Ubiquitin Vesicle absorption cohort experimental study extracellular human disease humanized mouse hypocupremia in vivo insight mouse model multicatalytic endopeptidase complex reconstitution response uptake

项目摘要

Copper (Cu) is an essential trace metal that is acquired from the diet and serves as a catalytic co-factor for a wide variety of enzymatic reactions that play critical roles in life. Cu deficiency leads to pathophysiological manifestations including impaired iron absorption, neutropenia, cognitive defects, peripheral neuropathy and hypertrophic cardiomyopathy. Understanding the mechanisms responsible for the accumulation of Cu in cells and tissues, the regulation of Cu accumulation, and the consequences due to dysregulated Cu acquisition are important to human health. Ctr1 is the only known Cu+ importer in mammals and while Ctr1 plays an essential role in dietary and peripheral Cu acquisition, embryonic development, cardiac function and normal growth, little is known about the mechanisms that regulate Ctr1 activity. Ctr1 exists both as a full-length protein and as a truncated form (tCtr1) lacking the extracellular Cu binding domain, which has reduced Cu uptake activity. We identified cathepsin as a protease that carries out the rate-limiting step in Ctr1 ecto-domain cleavage and demonstrated that this cleavage is stimulated by the Ctr2 integral membrane protein. Among patients in a large cardiac catheterization clinic cohort, we identified a single nucleotide polymorphism (SNP) in the human Ctr1 gene that occurs predominantly in African Americans, resulting in hyper-cleavage of the Ctr1 Cu-binding ecto-domain and decreased cellular Cu acquisition. Here we detail experiments to test the hypothesis that Ctr1 ecto-domain cleavage, through the cathepsin L/B proteases and Cu-responsive Ctr2 levels, is a critical regulatory mechanism for mammalian Cu acquisition. Our experiments will identify new components in mammalian Cu homeostasis, decipher a new mechanism for Cu- dependent proteolysis, generate a new animal model and validate a link between a defect in Ctr1 ecto-domain cleavage, Cu deficiency and hypertrophic cardiomyopathy in African Americans.

铜（Cu）是一种必需的微量金属，从饮食中获得，并作为催化剂在生命中发挥关键作用的各种酶反应的辅因子。铜缺乏导致包括铁吸收受损，中性粒细胞减少症，认知缺陷、周围神经病变和肥厚型心肌病。了解负责铜在细胞和组织中积累的机制，铜的调节积累，以及由于铜获取失调的后果是重要的，人体健康 Ctr 1是哺乳动物中唯一已知的Cu+输入者，而Ctr 1在哺乳动物中起着重要作用。饮食和外周铜的获取，胚胎发育，心脏功能和正常生长，很少有人知道的机制，调节Ctr 1活性。Ctr 1既作为全长蛋白和缺少胞外Cu结合结构域的截短形式（tCtr 1），其具有降低的Cu吸收活性。我们确定组织蛋白酶是一种蛋白酶， Ctr 1胞外域切割的限速步骤，并证明这种切割是由Ctr 2整合膜蛋白刺激。在大心脏病患者中，在导管插入门诊队列中，我们发现了一个单核苷酸多态性（SNP），在人类 Ctr 1基因主要发生在非洲裔美国人中，导致 Ctr 1 Cu结合胞外结构域和减少细胞Cu获得。在这里，我们详细的实验来测试的假设，Ctr 1胞外结构域切割，通过组织蛋白酶L/B蛋白酶和Cu响应性Ctr 2水平，是一个关键的哺乳动物铜获得的调节机制。我们的实验将发现新的哺乳动物铜稳态的组成部分，破译了一个新的机制铜- 依赖性蛋白水解，产生新的动物模型并验证缺陷非洲人Ctr 1胞外区裂解、铜缺乏和肥厚型心肌病美国人