THYROID PHYSIOLOGY STUDIES OF INHERITED DISORDERS

遗传性疾病的甲状腺生理学研究

• 批准号: 8049871
• 负责人: Samuel Refetoff
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049871
• 关键词: Adenoviruses; Adult; Affect; Animals; Behavior; Binding Proteins; Brain; Bypass; Cell Line; Cell membrane; Cells; Clinical; Clinical Research; Clinical Trials; Complement; Computer Simulation; Creatine; DNA Insertion Elements; Data; Defect; Detection; Development; Disabled Persons; Disease; Drug or chemical Tissue Distribution; Early identification; Early treatment; Embryo; Etiology; Evolution; Family; Female; Fetal Development; Fetus; Fibroblasts; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Counseling; Genetic screening method; Genetically Engineered Mouse; Genotype; Goals; Growth; Health; Hormones; Human; Immunohistochemistry; In Situ Hybridization; In Vitro; Inborn Genetic Diseases; Inbred Strains Mice; Infection; Inherited; Iodide Peroxidase; Label; Life; Link; Maps; Mediating; Mediation; Metabolic; Metabolism; Microarray Analysis; Morphology; Mothers; Motor; Mouse Strains; Mus; Mutation; Neuraxis; Nuclear; Organ; Patients; Peripheral; Phenotype; Physiology; Pregnancy; Prenatal Diagnosis; Process; Psychomotor Disorders; RNA Interference; Receptor Gene; Regulation; Reproduction; Research; Research Design; Research Personnel; Research Proposals; Resistance; Role; Screening procedure; Selenium; Selenocysteine; Severities; Small Interfering RNA; Staging; Supplementation; Syndrome; Testing; Therapeutic Intervention; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyroxine; Tissues; Transmembrane Transport; Traumeel S; Woman; base; clinical material; cofactor; creatine transporter; deiodination; handicapping condition; hormone metabolism; hormone sensitivity; in vivo; male; man; mouse model; mutant; offspring; prenatal; programs; receptor; response; selenocysteine insertion sequence binding protein 2; selenoprotein; skills; success; tumor

DESCRIPTION (provided by applicant): The broad objective of this research proposal is to advance understanding of thyroid physiology through study of genetic defects at key regulatory processes. More specifically, research is centered on the mediation of thyroid hormone (TH) effects by studying syndromes of reduced sensitivity to TH due to defects in cell membrane transport, metabolism and action caused by mutations in the MCT8 (monocarboxylate transporter), SBP2 (selenocysteine insertion sequence binding protein) and TR (nuclear TH receptor) or cofactors genes, respectively. These defects will be studied with a triple approach, clinical (in-vivo), tissue (in- vitro) and animal (genetically engineered mice) that complement and compensate for limitations inherent in each. 1). Clinical studies will correlate the central and peripheral tissue responses to the administration of the active TH, Ta and its precursor thyroxine (T,4) in order to determine organ and cell specific TH transport and metabolism. 2). Patient's fibroblasts, propagated in culture, will serve for the direct examination of iodothyronine specific transport across the cell membrane and their intracellular metabolism. The role of SBP2 in the hierarchy of selenoprotein synthesis will also be studied. Microarray analysis of TH action in fibroblasts will serve to identify differences in subjects with and without TRR gene mutations, in order to uncover the etiology of resistance to TH in the absence of TRB gene mutations and identify important cofactors. 3). Mice deficient in the Mct8 gene will serve to study in depth the thyroid and brain abnormalities responsible for the manifestations of MCT8 defects in man. Behavior and motor function will be tested, and central nervous system morphology will be examined by in-situ hybridization and immunohistochemistry. The discrepancy between the magnitude of thyroid and psychomotor disorders will be investigated to determine if they are causally linked. Mice with strain dependent differences in TH sensitivity will serve to identify putative modifiers of TH action. 4). Various means will be tested to revert or diminish the psychomotor defect of Mct8 deficiency. TH hormone will be given to Mct8 deficient mice at crucial stages of fetal development. TH conjugated to creatine will serve to deliver the hormone to brain through the creatine transporter, thus bypassing the TH transport defect. Selenium supplementation will be used in an attempt to increase the selenoprotein levels in SBP2 defects. Practical Significance: Clinical studies will characterize the phenotypes caused by these genetic defects, establishing criteria for genetic testing. Early identification of mutations will provide prenatal diagnosis and the basis for genetic counseling, particularly in MCT8 defects producing incapacitating illness in male offspring. Successful development of prenatal treatment would rescue affected males from this severe handicap. The prenatal detection of unaffected fetuses carried by women with TRS mutations will provide the option of early treatment.

描述（由申请人提供）：本研究提案的广泛目标是通过研究关键监管过程中的遗传缺陷来促进对甲状腺生理学的理解。更具体地说，研究集中在甲状腺激素（TH）作用的介导上，通过研究由于MCT8（单羧酸转运蛋白）、SBP 2（硒代半胱氨酸插入序列结合蛋白）和TR（核TH受体）或辅因子基因突变引起的细胞膜转运、代谢和作用缺陷而导致的对TH敏感性降低的综合征。这些缺陷将采用三重方法进行研究，即临床（体内）、组织（体外）和动物（基因工程小鼠），以补充和补偿各自固有的局限性。1）。临床研究将使中枢和外周组织响应与活性TH、Ta及其前体甲状腺素（T，4）的施用相关联，以确定器官和细胞特异性TH转运和代谢。2）的情况。患者的成纤维细胞，在培养中繁殖，将用于碘甲腺原氨酸特异性跨细胞膜转运及其细胞内代谢的直接检查。SBP2在硒蛋白合成层次中的作用也将被研究。成纤维细胞中TH作用的微阵列分析将用于鉴定具有和不具有TRR基因突变的受试者的差异，以揭示在不存在TRB基因突变的情况下对TH的抗性的病因并鉴定重要的辅助因子。3）。Mct8基因缺陷小鼠将用于深入研究导致人类MCT8缺陷表现的甲状腺和大脑异常。将测试行为和运动功能，并通过原位杂交和免疫组织化学检查中枢神经系统形态。将调查甲状腺疾病和精神疾病程度之间的差异，以确定它们是否存在因果关系。TH敏感性具有品系依赖性差异的小鼠将有助于识别TH作用的推定修饰剂。4）。将测试各种手段来恢复或减少Mct 8缺乏的心理缺陷。TH激素将在胎儿发育的关键阶段给予Mct8缺陷小鼠。与肌酸结合的TH将通过肌酸转运蛋白将激素递送到大脑，从而绕过TH转运缺陷。硒补充剂将用于尝试增加SBP2缺陷中的硒蛋白水平。实际意义：临床研究将描述这些遗传缺陷引起的表型，建立基因检测的标准。突变的早期鉴定将提供产前诊断和遗传咨询的基础，特别是在MCT8缺陷导致男性后代失能性疾病方面。产前治疗的成功发展将使受影响的男性摆脱这一严重障碍。产前检测TRS突变妇女携带的未受影响的胎儿将提供早期治疗的选择。