Condon Lab

The research in our lab centers around defining the molecular mechanisms responsible for the maintenance of uterine quiescence during pregnancy. We have isolated non-apoptotic Caspase-3 activation as a tocolytic event which maintains uterine quiescence across gestation through targeting specific components of the uterine myocyte contractile architecture and suppressing prostaglandin synthesis. The uterine endoplasmic reticulum response acts as the major regulator of Caspase-3 activation in the pregnant uterus. However we have found that preconditioning of this endoplasmic reticulum stress response maintains caspase activation in its critical, anti-contractile, tocolytic, non-apoptotic phenotype throughout gestation.

10% of pregnant women undergo preterm birth, and 40% of these preterm births are unexplained. We propose that the unexplained preterm births are caused by either the inability of uterine cells to precondition appropriately against the common stresses during pregnancy, such as hypoxia or stretching of the uterine wall, or an improper/incomplete pre-conditioning of the pregnant uterus. We suggest that the protective pre-conditioning mechanism of the uterine myocyte depends upon the generation and secretion of a distinct secretome. We have observed that the preconditioned phenotype can be propagated to other naive cell types in an endocrine and paracrine fashion. Robust paracrine dissemination of a preconditioned phenotype to adjacent unstressed/un-preconditioned uterine myocytes likely acts to build tolerance and tissue-type fidelity upon exposure to ensuing local insults experienced across gestation. The endocrine dissemination of the uterine preconditioning secretome likely promotes systemic adaptation to pregnancy. We are currently examining the mechanism and consequences of propagation of the preconditioned phenotype in vivo and in vitro.

Utilizing SILAC analysis followed by LC/MSMS we have identified several extracellular proteins secreted from the uterine myocyte during endoplasmic reticulum stress that act in an anti-inflammatory, pro-resolutionary manner. These circulating chaperone proteins target macrophage polarization and cytokine production to ensure suppression of a pro-inflammatory phenotype, which promotes uterine quiescence. We are currently examining the functional relevance of these secreted extracellular proteins with respect to gestational length in our pregnant mouse models of term and preterm birth. We are also examining the levels of these circulating proteins in the serum of pregnant women who deliver at term and preterm. Pregnant women at who underwent idiopathic preterm birth were demonstrated to have significantly decreased serum levels of these circulating factors. This is highly attractive from a clinical viewpoint and as a tocolytic strategy as we ultimately aim to identify local and systemic adaptations that may serve as preconditioning stimuli to restore appropriate preconditioning profiles in order to prolong uterine quiescence in women at risk for preterm birth but also affords a unique opportunity for non-invasive preterm birth associated biomarker discovery.

Blocking estrogen receptor signals in pregnancy may be key to preventing early contractions leading to prematurity SHARE
Dr. Condon wins grant to study novel preterm labor prevention agent
Dr. Condon wins President’s Award from Society for Reproductive Investigation