GLUCOCORTICOID RECEPTOR--STRUCTURE AND FUNCTION

候选人马克·丹尼尔森博士是最近任命的助理 这个系的教授。他的R01的第一年很有成效 他已经开始与其他研究小组开展合作 在这所大学内外都是如此。该部门将一个非常重要的 非常重视研究，并认识到年轻教职员工需要 在他们成长的几年里提供支持，如果他们想要发展一个享有盛誉的 和资金充足的研究项目。教学/委员会的工作负担很轻 头一两年，然后稳步增加。如果RCDA获奖 部门承诺不应超过其工作时间的10%。目前50% 他的时间都花在了非研究活动上，这将 毫无疑问，在没有RCDA的情况下，这一数字会增加。如果RCDA获奖 该部将通过为以下方面提供资金进一步支持候选人 包括人员和补给。这应该使丹尼尔森博士能够开发出 许多新项目和合作项目不是由他资助的 当前R01。 这项建议侧重于糖皮质激素的激素结合域。 受体(GR)，旨在阐明以下问题： 1)激素结合部位的结构决定因素是什么？2) 激素结合是如何激活受体的？ 这个问题将通过两种方式解决。首先，混合受体将 主要是GR，但有小区域的 孕激素或雄激素受体结合结构域取代GR 序列。这些受体将被分析其结合能力。 GR激动剂和拮抗剂(包括孕酮)和雄激素。 当结合发生时，激素激活受体的能力将 被研究。第二种方法是在组织培养中选择细胞 包含突变的受体，这些受体a)变得不依赖激素，或者 B)需要降低荷尔蒙水平，或c)可以有效地激活 通常是部分激动剂和/或拮抗剂的化合物。这些 受体将通过克隆和测序来表征。作为一个长期的 投影GR和选定的杂交种/突变体的激素结合域 将在过量表达系统中表达以产生足够的 用于结构研究的蛋白质。

The candidate, Dr. Mark Danielsen, is a recently appointed Assistant Professor in this Department. The first year of his R01 was productive and he has begun to develop collaborations with other research groups both within and outside this University. The Department places a very strong emphasis on research and recognizes that younger faculty require support during their formative years if they are to develop a prestigious and well funded research program. Teaching/committee loads are light in the first year or two and then steadily increase. If an RCDA is awarded Department commitments should not exceed 10% of his time. At present 50% of his time is taken up with non-research activities, and this would undoubtedly increase in the absence of an RCDA. If an RCDA is awarded the Department will further support the candidate by providing funds for both personnel and supplies. This should enable Dr. Danielsen to develop a number of new projects and collaborations that are not funded by his current R01. This proposal focuses on the hormone binding domain of the glucocorticoid receptor (GR) and is designed to shed light on the following questions: 1) What are the structural determinants of the hormone binding site? 2) How does hormone binding activate the receptor? The problem will be approached in two ways. First, hybrid receptors will be made which are mainly GR but which have small regions of either the progesterone or androgen receptor hormone binding domain replacing the GR sequence. These receptors will be analyzed for their ability to bind to GR agonists and antagonists (including progesterone) and to androgens. When binding occurs, the ability of the hormone to activate receptor will be studied. The second approach is to select for cells in tissue culture that contain mutant receptors that have a) become hormone independent, or b) require reduced levels of hormone, or c) can be activated efficiently by compounds that are usually partial agonists and/or antagonists. These receptors will be characterized by cloning and sequencing. As a long term project the hormone binding domain of the GR and selected hybrids/mutants will be expressed in an overexpression system to produce sufficient protein for structural studies.