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The pathophysiology of SBP2 abnormalities

SBP2异常的病理生理学

基本信息

批准号：
8060110
负责人：
Alexandra Mihaela Dumitrescu
金额：
$ 5.68万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8060110
关键词：
Address Affect Age Aging Alleles Animal Model Animals Antioxidants Bilateral Binding Proteins Biochemical Biology Brain Breeding Bypass C-terminal Characteristics Child Cis-Acting Sequence Codon Nucleotides Complex DNA Insertion Elements Defect Development Developmental Delay Disorders Embryo Engineering Equilibrium Exons Family Fertility Functional disorder Gene Mutation Generations Genes Genetic Recombination Growth Histology Human Immune System Diseases In Vitro Individual Infertility Investigation Iodide Peroxidase Iodothyronine Deiodinase Knock-in Mouse Knockout Mice Life Malignant Neoplasms Measurement Measures Mediating Medical Mental Retardation Messenger RNA Methods Modeling Monitor Motor Mus Muscle Mutation Myopathy Neck Neurodegenerative Disorders Oxidation-Reduction Oxidative Stress Oxidoreductase Pathology Pathway interactions Patients Pattern Phenotype Physiological Process Property Regulation Reporting Research Respiratory Insufficiency Selenium Sensorineural Hearing Loss Serum Site Staging System Tamoxifen Techniques Test Result Testing Therapeutic Thyroid Function Tests Thyroid Gland Thyroid Hormones Tissues Trans-Activators Transgenic Mice design glutathione peroxidase hormone metabolism human disease in vivo indexing insight mouse model mutant postnatal prenatal promoter scoliosis selenium deficiency selenocysteine insertion sequence binding protein 2 selenoenzyme selenoprotein sperm cell thioredoxin reductase tool wasting

项目摘要

DESCRIPTION (provided by applicant): Project Summary The human selenoproteome comprises at least 25 selenoproteins. The majority are selenoenzymes that require selenium (Se) in the form of Selenocystein (Sec) for proper enzymatic activity. Some serve as antioxidants or oxido-reductases [glutathione peroxidases (GPx) and thioredoxin reductases], in thyroid hormone metabolism (deiodinases), in Se transport, storage, and delivery to the brain (SePP) and in sperm viability (PHGPx). The machinery for Sec incorporation recodes the UGA codon and requires cis-acting sequences present in the mRNA of all selenoproteins, the in frame UGA and the Sec insertion sequence (SECIS), while Sec-specific tRNASec, and SECIS-binding protein (SECISBP2 or SBP2) are some of the required trans-acting factors. SBP2 is believed to be the major determinant of Sec incorporation as its immunodepletion eliminates Sec incorporation. A not well understood but distinct hierarchy exists in the synthesis of selenoproteins as their expression is differentially affected by Se deficiency, and preferential SECIS recognition by SBP2 was demonstrated. Important medical clues to the consequences of impaired selenoprotein synthesis became apparent with the report of mutations in the SBP2 gene, causing partial SBP2 deficiency in children of several families. Affected subjects presented with transient growth delay and abnormal thyroid function tests resulting from altered thyroid hormone metabolism due to deficiency in the deiodinases. New reports of SBP2 gene mutations describe additional features, a complex phenotype with congenital myopathy and developmental delay in one case, and azoospermia, sensorineural hearing loss in another, thus reflecting multiple selenoprotein deficiencies. Animal models for this new genetic defect are required to answer the many questions raised by the human phenotype. To address this need, I designed a research plan to generate mouse models with Sbp2 deficiency, using recombineering techniques. As redundancy in SBP2 function was not found in-vitro and lack of SBP2 is putatively lethal, I will engineer a Sbp2KI mouse for a C- terminus mutation reported in a patient with a severe phenotype, and an inducible Sbp2KO mouse. The unlimited access to tissues will help distinguish in-vivo the different layers of regulation and selenoprotein hierarchy. Initial investigations of these mice will uncover the underlying mechanisms for the thyroid phenotype, infertility, growth delay, the importance of the putative C-terminal functional domain in-vivo, and the specific cause for the myopathy. The study of the ageing animals will allow close monitoring for manifestations later in life, and other presumed phenotypes, including cancer, neurodegenerative disorders and immune dysfunction. These investigations are relevant to multiple physiological functions and pathways, and will help elucidate the mechanisms underlying selenoprotein-mediated pathology. Ultimately, these animal models will make possible in-vivo testing of various compounds with potential therapeutic properties applicable to humans, thus making this model a necessary tool. PUBLIC HEALTH RELEVANCE: A unique insight into selenoprotein biology was provided by the recent identification of SBP2 gene mutations in humans. The different layers of selenoprotein regulation and hierarchy will be defined by studying the phenotype of an Sbp2 gene knock-in mouse model and that of temporally controlled and tissue specific Sbp2 gene knock-out mouse. These investigations are relevant to multiple physiological functions and pathways, and will help elucidate the mechanisms underlying selenoprotein-mediated pathology

描述（由申请人提供）：项目概要人类硒蛋白质组包含至少 25 种硒蛋白质。大多数是含硒酶，需要硒代半胱氨酸 (Sec) 形式的硒 (Se) 才能发挥适当的酶活性。有些在甲状腺激素代谢（脱碘酶）、硒运输、储存和递送至大脑 (SePP) 以及精子活力 (PHGPx) 中充当抗氧化剂或氧化还原酶 [谷胱甘肽过氧化物酶 (GPx) 和硫氧还蛋白还原酶]。 Sec 掺入机制重新编码 UGA 密码子，并需要所有含硒蛋白 mRNA 中存在的顺式作用序列、框内 UGA 和 Sec 插入序列 (SECIS)，而 Sec 特异性 tRNASec 和 SECIS 结合蛋白（SECISBP2 或 SBP2）是一些所需的反式作用因子。 SBP2 被认为是 Sec 掺入的主要决定因素，因为其免疫耗竭消除了 Sec 掺入。硒蛋白的合成中存在一个尚未充分理解但明显的层次结构，因为它们的表达受到缺硒的不同影响，并且证明了 SBP2 优先识别 SECIS。随着 SBP2 基因突变的报道，有关硒蛋白合成受损后果的重要医学线索变得显而易见，该突变导致几个家庭的儿童部分 SBP2 缺乏。受影响的受试者出现短暂的生长迟缓和甲状腺功能测试异常，这是由于脱碘酶缺乏导致甲状腺激素代谢改变所致。 SBP2基因突变的新报告描述了其他特征，一种复杂的表型，其中一个病例患有先天性肌病和发育迟缓，另一个病例患有无精症、感音神经性听力损失，从而反映了多种硒蛋白缺乏。这种新的遗传缺陷的动物模型需要回答人类表型提出的许多问题。为了满足这一需求，我设计了一项研究计划，利用重组工程技术生成 Sbp2 缺陷的小鼠模型。由于在体外没有发现 SBP2 功能的冗余，并且缺乏 SBP2 被认为是致命的，因此我将针对严重表型患者报告的 C 末端突变设计一只 Sbp2KI 小鼠，以及一只可诱导的 Sbp2KO 小鼠。对组织的无限访问将有助于区分体内不同的调节层和硒蛋白层次结构。对这些小鼠的初步研究将揭示甲状腺表型、不育、生长延迟的潜在机制、体内假定的 C 端功能域的重要性以及肌病的具体原因。对衰老动物的研究将允许密切监测晚年的表现以及其他推测的表型，包括癌症、神经退行性疾病和免疫功能障碍。这些研究与多种生理功能和途径相关，并将有助于阐明硒蛋白介导的病理学的潜在机制。最终，这些动物模型将使对具有适用于人类的潜在治疗特性的各种化合物进行体内测试成为可能，从而使该模型成为必要的工具。公共健康相关性：最近在人类中发现的 SBP2 基因突变为硒蛋白生物学提供了独特的见解。通过研究 Sbp2 基因敲入小鼠模型和时间控制和组织特异性 Sbp2 基因敲除小鼠的表型，将定义不同层次的硒蛋白调控和层次结构。这些研究与多种生理功能和途径相关，并将有助于阐明硒蛋白介导的病理学的潜在机制