1. Uterine smooth muscle (myometrium) energy metabolism
The contractility required for cervical dilation and expulsion of the fetus during labor – lasting for hours to days in humans – places a high energy demand on the uterine muscle (myometrium). Other muscles with high energy demands, such as skeletal muscle during exercise and cardiac muscle, differ in which substrates they use to produce ATP. However, we lack knowledge regarding myometrial energy substrate preferences. Thus, we are interested in understanding the energy substrate preferences and metabolic flexibility of the myometrium during labor. This will allow us to then study how metabolic needs are met and whether they are dysregulated in pathologic states such as prolonged labor, maternal obesity or diabetes. Some of the questions we are working on answering:
- What are the myometrial energy substrate preferences in the quiescent versus contractile state?
- What effect does maternal obesity have on spontaneous and uterotonic-induced myometrial contractility?
- How does maternal obesity affect metabolic fuel preference in mitochondria from myometrium at different points in gestation?
- What is the role of mitochondrial fission and fusion in myometrial function?
2. Role of Sphingosine-1-phosphate in myometrial contractility
The lipid sphingosine-1-phosphate (S1P) is a multi-functional signaling molecule produced intracellularly via a conserved metabolic pathway. Sphingolipids and the receptors they bind have been implicated in multiple reproductive processes, including corpus luteum function, endometrial decidualization, trophoblast invasion, and embryonic development. We have recently found that sphingolipid metabolism is activated during parturition in both mice and humans. Furthermore, inhibition of this pathway can delay inflammatory-stimulated preterm birth in mice. Our work using human myometrium showed that S1P mediates the proinflammatory response development in a contractile myometrium. Development of novel pharmacological regulators of sphingolipid metabolism and signaling might provide alternative therapeutic approaches to alter uterine contractility for treatment of preterm labor and labor dystocia. Some of the questions we are working on answering:
- What effect dose acute S1P receptor inhibition have on myometrial contractility?
- What effect does S1P signaling have on uterine tissue inflammatory cell infiltration during term and preterm labor?
- How is S1P regulated in blood and gestational tissues throughout human pregnancy?
- How do pathologic labor states affect S1P metabolism?
3. Oxytocin
In the US, nearly half of all pregnant women are treated with a synthetic version of the neuropeptide oxytocin to induce or augment labor or prevent postpartum hemorrhage. However, women require a wide range of oxytocin doses to elicit an appropriate degree of uterine contractility. Furthermore, the oxytocin receptor (OXTR) can cease responding to oxytocin (become desensitized) after long-term oxytocin administration, often leading to the need for cesarean delivery. Understanding the molecular mechanisms of OXTR trafficking and activation in myometrial cells can help us improve labor management strategies. Some of the questions we are working on answering:
- What are the mechanisms of OXTR desensitization and inactivation in the myometrium after prolonged agonist exposure? Can we manipulate these to increase OXTR recycling?
- What is the role of posttranslational modifications (glycosylation, ubiquitination) of OXTR in its trafficking and function?
- What are the kinetics of OXTR trafficking – internalization, recycling, degradation?
