Grant: Project Grant

Preterm birth (PTB) occurs in >10% of all births, and fetal inflammation (FI) in at least 40% of PTBs. Both are major causes of child death <5 years and of life-long morbidity. PTB and FI are unmet medical needs without effective diagnostics or therapeutics. Fortunately, Olson and Chemtob have each independently developed a diagnostic and therapeutic, respectively, that are complementary since the former is stimulated by the upstream mediator of PTB and FI, interleukin-1b, or IL1b, and the latter blocks IL1b action. Olson's diagnostic, the Leukocyte Migration Assay (LMA), uses white blood cells collected from pregnant women who are at risk of PTB or FI. By counting the number of cells that migrate to a stimulus extracted from the placental membranes, we can predict with precision women who will deliver within 7 days. Chemtob has designed a small peptide drug, rytvela, that blocks the action of IL1b and stops leukocyte migration in the LMA. We predict that IL1b stimulates PTB & FI in the pregnant mouse, that this is diagnosed by the LMA, and that rytvela is able to block PTB & FI and protect the fetus for normal birth, growth and development. We will perform three tests. In the first, we will stimulate PTB & FI in pregnant mice with powerful activators of silent or infectious inflammation. Then we will determine whether the LMA diagnoses PTB & FI and whether rytvela blocks these and restores maternal and fetal health. In the second, we will use a very low dose of IL1b to create a chronic fetal inflammation model without PTB. Again we will test whether the LMA detects this FI and whether rytvela improves fetal outcomes. In the last aim, we will study the chemotactic attraction molecules called chemokines stimulated by IL1b in human placental membranes to identify those key for attracting leukocytes at PTB. We will also identify how leukocytes are activated by IL1b and the key chemokines. This information will lead to human trials for a new diagnostic and therapeutic.