Estrogen receptor Alpha/Beta antagonism in osteoblasts

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Estrogen is a key regulator in the growth
and maintenance of bone mass in both sexes. Two isoforms of estrogen receptor,
ERalpha and ERbeta, mediate the transcriptional effects of estrogen by binding
1 7-beta.estradiol (E2) and subsequently binding to specific elements within
the regulatory regions of genes. Although we, and others, have shown that
ERalpha and ERbeta are functional in osteoblasts, little data are available
concerning the interactions of ERalpha and ERbeta in bone. Recent gene deletion
experiments in mice suggest that the ERalpha and ERbeta isoforms may have
opposing actions on bone, by analogy with the A and B isoforms of PR, where
PR-A is an inhibitor of PR-B. One mechanism to explain the potential
antagonistic effects of ERalpha and ERbeta would involve the differential
recruitment of steroid receptor coactivators (SRCs), which transmit the
transcriptional signal to the basal transcriptional machinery. Therefore, the
purpose of this research proposal is to understand the functions of
ERalpha/alpha and ERbeta/beta homodimers in human osteoblasts and to understand
the effects of the ERalpha/beta heterodimer on gene transcription in human
osteoblasts. The project will attempt to address these basic biological
questions using three approaches: 1) to understand the effects of ERalpha/beta
heterodimers on the transcriptional potential at canonical estrogen response
elements (EREs) and at SP1/(ERE1/2) sites in hFOB and MG-63 cell lines; 2)
determine the recruitment of steroid receptor coactivators (SRCs) by various ER
homo- and heterodimers; and finally 3) determine the in vivo consequences of
ERalpha/alpha, ERbeta/beta and ERalpha/beta expression in human OB cells using
gene chip technology.
StatusNot started


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