Nuclear cofactors in Human Thyroid Disease

描述（由申请人提供）：本申请是面向患者研究（K24）的职业中期研究者奖。它旨在为Roy Weiss作为临床研究者提供支持，使他能够专注于以患者为导向的研究，并作为初级临床研究者的导师。Weiss博士作为临床研究者和医学生、住院医师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助因子在人类甲状腺生理和疾病调节中的作用。甲状腺激素（TH）是成年人正常生长发育和维持代谢活动所必需的。甲状腺激素作用是由核内甲状腺激素受体（TRs）调节激素应答基因的转录介导的。共调节因子是与配体或非配体核受体相互作用以进一步调节TR靶基因转录的核蛋白。这些共调节因子可能是在缺乏TH时抑制转录的辅抑制因子，也可能是刺激配体TR转录激活的辅激活因子。指导本研究的假设是，参与介导TH作用的辅因子或TRs的缺陷导致甲状腺激素反应性疾病的表现，即TH抵抗（RTH）和TH超敏反应。我们建议：(1)在体内寻找有或没有TR突变的RTH患者对糖皮质激素和性激素的微妙耐药。识别这些缺陷将有助于确定人体内特定辅助因子的功能。(2)确定RTH表型的变异性是否由于调节TH作用的辅助因子的差异。(3)确定TH超敏的原因。这将使临床医生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.