Nuclear cofactors in Human Thyroid Disease

描述(由申请者提供)：本申请是关于以病人为中心的研究的职业生涯中期奖(K24)。它的目的是为Roy Weiss作为临床调查员提供支持，将重点时间投入到以患者为导向的研究中，并作为初级临床调查人员的导师。韦斯博士作为医学生、住院医生和研究员的临床研究员和导师的成就使这一目标成为现实。这项研究计划是为了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)对成人的正常生长发育和代谢活动的维持是必不可少的。TH的作用是通过调节激素反应基因转录的核内甲状腺激素受体(TRs)来实现的。辅调节因子是一种核蛋白，它与连接或非连接的核受体相互作用，进一步调节转录因子受体靶基因的转录。辅调节因子既可以是辅抑制子，在没有TH的情况下抑制转录，也可以是辅活化子，刺激连接的TRR的转录激活。指导这项研究的假设是，参与TH作用的辅因子或TRs的缺陷是甲状腺激素反应性疾病的表现，即对TH的抵抗(RTH)和对TH的超敏。建议：(1)在体内寻找伴有和不伴有TRR突变的RTH患者对糖皮质激素和性激素的微妙抵抗。识别这些缺陷将有助于确定特定辅因子在人体内的功能。(2)确定RTH表型的变异性是否源于调节TH作用的辅助因素的差异。(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。

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.