Stimulation of Estrogenic Responses
Kenneth Korach, Ph.D. leads the Receptor Biology Group. The group works to identify the estrogenic responses in target cells and to evaluate the different cellular mechanisms involved in their activation.
Environmental agents produce a variety of effects on the reproductive tract, some of which result in infertility and toxicity. In many cases such effects are direct and are produced by agents having estrogenic hormonal activity, but with little structural resemblance to the natural ligand. Mechanistically, hormonal activity is believed to be mediated through intracellular receptor proteins, although the tissues and specific responses vary, a primary response is alterations in gene transcription. The receptor demonstrates specific stereochemistry for endogenous compounds but appears to interact less selectively with exogenous chemicals.
To better understand such differences, studies are underway to determine a structural and chemical basis for the stimulation of estrogenic responses and the involvement of the estrogen receptor in this process. A variety of organ systems and tissues are investigated including the male and female reproductive tract, bone, cardiovascular, immune, prostate, lung, neuroendocrine and neurological sites. Reproductive tract tissue is a principal target site of estrogen action related to hormone responsiveness being investigated at the biochemical and molecular level. Several tissues have been known to be susceptible and sensitive to estrogen withdrawal and treatment. Until recently the effect was believed to be indirect, however, the description of estrogen receptors in these tissues indicates estrogen can act directly. Investigations are intended to identify the estrogenic responses in target cells and evaluate the different cellular mechanisms involved in their activation. Experimental approaches involve the following techniques: tissue culture, transgenic animal models including insertional gene targeting and knock-out mouse lines, nucleic acid biochemistry and gene cloning, intracellular signaling, protein biochemistry, purification and characterization.
Major areas of research:
- Ligand binding to nuclear estrogen receptor interactions and its role in stimulating estrogenic responses
- Processes involved in the activation of the estrogen receptor and its role in mediating biological responses
- Determining estrogen hormonal tissue responses
- Evaluating environmental hormonal diseases and dysfunction
- Examining the influence of different ligand structures and receptor forms on the regulation of exogenous hormonally responsive reporter gene constructs
- Analyzing the regulated expression of gene networks in different tissues by estrogen evaluated by microarray analyses
- Investigating the expression of uterine estrogen responses and evaluating the possible coupling of other signal transduction mechanisms
Kenneth Korach, Ph.D., leads the Receptor Biology Group within the Laboratory of Reproductive and Developmental Toxicology. He received his Ph.D. in endocrinology from the Medical College of Georgia. He has edited four books and published 280 peer-reviewed articles in leading biomedical journals as well as several book chapters. He served as a Ford Research Fellow at Harvard Medical School before joining NIEHS in 1976.