Nuclear cofactors in Human Thyroid Disease

人类甲状腺疾病中的核辅因子

• 批准号: 6600187
• 负责人: ROY E WEISS
• 金额: $ 9.86万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6600187
• 关键词: clinical research; cofactor; gene induction /repression; gene mutation; genetic regulatory element; hormone regulation /control mechanism; hormone sensitivity /resistance; human subject; nuclear receptors; patient oriented research; thyroid disorder; thyroid hormones

DESCRIPTION (provided by applicant): This application is for a Midcareer Investigator Award in Patient-Oriented research (K24). It is intended to provide support for Roy Weiss as a clinical investigator to devote focused time for patient orientated research and to act as a mentor for beginning clinical investigators. Dr. Weiss' accomplishments as a clinical investigator and mentor for medical students, residents and fellows make this goal realistic. The research plan is to investigate the role of nuclear cofactors regulating thyroid physiology and disease in man. Thyroid hormone (TH) is essential for normal growth and development as well as maintenance of metabolic activity in the adult. TH action is mediated by intranuclear thyroid hormone receptors (TRs) which regulate the transcription of hormone responsive genes. Coregulators are nuclear proteins which interact with liganded or unliganded nuclear receptors to further modulate the transcription of TR targeted genes. The coregulators may either be corepressors, which inhibit transcription in the absence of TH, or coactivators which stimulate transcriptional activation of the liganded TR. The hypothesis guiding the proposed studies is that defects in cofactors or TRs involved in the mediation of TH action are responsible for the manifestation of diseases of thyroid hormone responsiveness, namely, resistance to TH (RTH) and hypersensitivity to TH. It is proposed to: (1) search in vivo for subtle resistance to glucocorticoids and sex hormones in patients with RTH with and without TR mutations. Identification of such defects will help define the in vivo function of specific cofactors in man. (2) Determine if variability in the phenotype of RTH is due to differences in cofactors that modulate TH action. (3) Determine the cause for hypersensitivity to TH. This will allow clinicians to better identify factors influencing thyroid function.

描述（由申请人提供）：此应用程序是在以患者为导向的研究（K24）的中期职业生涯研究者奖。其目的是为Roy韦斯作为临床研究者提供支持，以便将重点时间用于以患者为导向的研究，并作为开始临床研究者的导师。韦斯博士作为临床研究者和医学生、住院医生和研究员的导师所取得的成就使这一目标成为现实。研究计划是研究核辅因子在调节人类甲状腺生理和疾病中的作用。甲状腺激素（TH）对成人的正常生长和发育以及维持代谢活动至关重要。TH作用由调节激素应答基因转录的核内甲状腺激素受体（TRs）介导。辅调节子是与配体或非配体核受体相互作用以进一步调节TR靶向基因的转录的核蛋白。辅调节子可以是辅阻遏物，其在TH不存在的情况下抑制转录，或者是辅激活物，其刺激配体TR的转录激活。指导拟议研究的假设是，参与TH作用介导的辅因子或TR的缺陷是甲状腺激素反应性疾病的表现，即TH抵抗（RTH）和TH超敏反应的原因。建议：（1）在体内寻找有和没有TR突变的RTH患者对糖皮质激素和性激素的微妙耐药性。这种缺陷的鉴定将有助于确定特定辅因子在人体内的功能。（2）确定RTH表型的变异性是否是由于调节TH作用的辅因子的差异。(3)确定对TH过敏的原因。这将使临床医生能够更好地识别影响甲状腺功能的因素。