Structure-function analysis of nuclear receptor and cofactor action: evidence for a role in muscle.

激素受体通过将激素的作用转化为代谢反应，在生理学的几乎所有方面都起着关键作用。人类有大约45种由不同基因编码的孤儿激素受体，由于所有受体在人类疾病的治疗中都很重要，过多的孤儿受体已经成为一种新范式——反向内分泌学发展的催化剂。反向内分泌学是利用孤儿激素受体来寻找以前未知的激素和代谢途径的过程。我们感兴趣的是孤儿激素受体，Rev-erbA和RVR，受体超家族的孤儿成员。rev - erbb α的表达受贝特类药物、广泛使用的降血脂药物和昼夜周期的调节。Rev-erbs介导脂质代谢和过氧化物酶体氧化的调节。此外，Rev-erbs在大脑癫痫发作时被急性诱导，被认为可以调节小脑的可塑性，并参与生长控制。鉴于这些关键的调节作用，以及迄今为止反向内分泌学的成功，我们打算完成Rev-erb和RVR的结构分析，作为识别结合该受体的激素的工具。激素受体招募一种叫做核受体辅助因子的蛋白质，这种蛋白质起着调节基因表达的作用。辅助因子调节基因的表达和发育。此外，当这些辅助因子调节不当时，会导致疾病和致癌的发生，这强调了对其在许多组织中的功能进行高分辨率观察的必要性。沿着这些思路，我们对检查这些辅助因子在肌肉中的功能很感兴趣。了解NR辅助因子在肌肉分化过程中的分子作用将是阐明这些蛋白在肌肉疾病（如横纹肌肉瘤和炎性肌病）中失调功能的关键一步，这些疾病都有辅助因子缺乏。

Hormone receptors have critical roles in almost all aspects of physiology by transducing the effects of hormones into metabolic responses. There are ~45 orphan hormone receptors encoded by distinct genes in humans, since all receptors are important in the treatment of human disease, the plethora of orphan receptors has been the catalyst for the development of a new paradigm, reverse endocrinology. Reverse endocrinology is the process whereby the orphan hormone receptor is used to search for a previously unknown hormone, and metabolic pathway. We are interested in the orphan hormone receptors, Rev-erbA and RVR, orphan members of the receptor superfamily. Rev-erb alpha expression is regulated by fibrates, widely used hypolipidemic drugs, and the circadian cycle. Rev-erbs mediate the regulation of lipid metabolism and peroxisomal beta oxidation. Furthermore, Rev-erbs are acutely induced during brain seizures, postulated to regulate cerebellar plasticity, and involved in growth control. In view of these critical regulatory roles, and the success of reverse endocrinology to date, we intend to complete the structural analysis of the Rev-erb and RVR as a tool to identify the hormone that binds this receptor. Hormone receptors recruit proteins called nuclear receptor cofactors, that function as regulators of gene expression. The cofactors regulate gene expression and development. Furthermore these cofactors, when misregulated result in the onset of disease and carcinogenesis, which underscores the need for achieving a high resolution view of their function in many tissues. Along these lines, we are interested in exmining the function of these cofactors in muscle. Understanding the molecular role of the NR cofactors during muscle differentiation will be a critical step toward elucidating the dysregulation-function of these proteins in muscle diseases, such as rhabdomyosarcoma and inflammatory myopathy that have cofactor deficiency.