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.
