Grant: Project Grant

Preterm birth, which is the leading cause of death of children under 5-year-old worldwide, involves the obligatory mediator: prostaglandin F2alpha receptor (FP), a lipid mediator receptor that controls the onset of uterus contraction. In Canada, preterm birth has increased by 20 % in the last two decades and accounts for two-thirds of the infant death. The cause of more than 70% of preterm birth is unknown, and the medications to prevent preterm birth are ineffective. FP represents a potential target to develop better and safer tocolytics (labour repressants) with a new class of drugs selectively targeting regulators of uterine contraction. However, the rational design of tocolytics targeting FP signalling in such manner has remained a challenge due to the dearth of information about the FP receptor architecture, especially about its interaction with ligands and signaling effectors. We propose to further characterize the 3-dimensional structural changes that occur in FP when it triggers these cellular signals using biophysical approaches such as X-ray crystallography. We will then use this structural information to create pharmacological tools that will interfere with these cellular signals induced by FP receptor. This proposal should give us means to further understand which of the cellular signals induced by FP receptor is directly implicated in the uterus contraction. Also, it could form the chemical basis for the development of a new therapy to prevent preterm birth.