The molecular mechanisms that regulate the timing of pre-term and term birth.Date Added: 4/6/2011 2:16:00 PM
Last Updated: 4/14/2011 11:22:00 AM
Description of projects available to graduate students:
The work in our laboratory is focused on determining the molecular mechanisms that regulate the timing of both term and pre-term birth.
Preserving the uterus in a state of relative quiescence is vital to the maintenance of a successful pregnancy. Circulating hormones such as progesterone play a critical role in maintaining uterine quiescence throughout pregnancy. We have recently found that uterine caspase-3 is a progesterone regulated target gene and have defined that elevated cytoplasmic levels of uterine caspase-3 activity during pregnancy act to preserve uterine quiescence through targeting and disabling components of the uterine contractile architecture in a reversible and in a non-apoptotic manner. We have observed very high levels of uterine caspase-3 during the pregnancy which disappear to barely detectable levels just before the onset of labor. Although activation of caspase-3 is typically associated with the onset of apoptosis, other studies have identified caspase-3 as a negative regulator of myocyte contractility in cardiac, skeletal and smooth muscle, without resulting in cell death. Similarly in the pregnant uterus we have found that despite highly elevated levels of uterine caspase-3 there is minimal apoptotic cell death.
The focus of this rotation opportunity is to define the events regulating the activation and persistence of the tocolytic action of uterine caspase-3. Our preliminary findings indicate that activation of the endoplasmic reticulum stress response potentiates uterine caspase activation. Accumulation of unfolded proteins in the endoplasmic reticulum represents a cellular stress induced by multiple stimuli. These include hypoxia, mechanical stretch and myocyte hypertrophy, triggering an evolutionarily conserved response termed the unfolded protein response (UPR).
We hypothesize that a defective activation or precocious inhibition of the UPR during pregnancy may limit the tocolytic potential of uterine caspase signaling resulting in the onset of pre-term birth. In defining the upstream events of uterine caspase-3 activation we hope to isolate target pathways that may be utilized as predictors of downstream caspase tocolytic potential. We speculate that these pathways may reveal translational avenues for potential future tocolytic drug design. With the growing recognition of an association of endoplasmic reticulum stress with human disease and with increased understanding of the fundamental mechanisms regulating endoplasmic reticulum stress, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge and may ultimately be utilized to reveal indicators of and the resolution of pre-term birth.
Techniques graduate student will learn:
The following techniques will be used during the rotation, though prior experience with all of these techniques is not essential.
Western Blot Analysis
Cell Biology And Molecular Physiology
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