|
• Toll-Like Receptor Antagonism as a Potential Treatment for Preterm Labor
• New Model of Ascending Infection Related Preterm Birth
• Global Alliance for the Prevention of Prematurity and Stillbirth
Toll-Like Receptor Antagonism as a Potential Treatment for Preterm Labor
Kristina Adams Waldorf, MD; Michael Gravett, MD (Co-investigator/Mentor)
The main objective of this research is to determine whether the innate immune response to intra-amniotic infection is a critical event in the pathogenesis of infection-induced preterm labor and fetal acute lung injury (ALI). Intra-amniotic infection causes the majority of early preterm births, which represent a significant economic and public health burden. Immune responses to bacteria are thought to drive infection-induced preterm labor and no therapy exists to prevent preterm birth.
The proposed study will determine the efficacy of a novel immunomodulator to prevent infection-induced preterm birth and fetal ALI by blocking the earliest immune response and may result in an effective treatment for preterm labor. The unifying hypothesis is that blockade of innate immune responses by intra-amniotic infusion of a toll-like receptor 4 (TLR4) antagonist will inhibit uterine activity and fetal ALI due to lipopolysaccharide (LPS) in our chronically catheterized nonhuman primate (NHP) model. LPS is a gram-negative bacterial product recognized by TLR4, an innate immune receptor. Antagonism of TLR4 in an LPS model allows investigation of the specific effect of innate immune response blockade on preterm labor and fetal ALI.
Investigating a new drug targeting infection-induced preterm birth and fetal ALI based on well-defined immunologic mechanisms may result in an effective treatment for preterm labor.
Funding Source: NIH
Contact: Kristina M Adams Waldorf
Ends 3/14/12
Top of Page
New Model of Ascending Infection Related Preterm Birth
Kristina Adams Waldorf, MD; Michael Gravett, MD (Co-Principle Investigator)
Preterm birth remains a significant economic and public health burden and the incidence is rising. Infection induced inflammation plays a significant role in preterm birth and is thought to occur as a result of either direct microbial infection or microbial byproduct stimulation of inflammatory mediators, which promotes premature myometrial responses and uterine contractions. Intra-amniotic infection (IAI) is thought to be the result of ascending bacterial infection from the vagina, and immune responses to bacteria are thought to drive preterm labor and promote fetal acute brain and lung injury.
Obstetrical research has yet to identify effective preventive interventions for preterm labor. The overall objective of this proposal is to develop a model system which emulates human preterm birth to ultimately elucidate molecular mechanisms of infection-induced preterm labor and related adverse neonatal sequelae (e.g. brain injury). We propose to develop a nonhuman primate model in the rhesus monkey that closely mimics an ascending lower genital tract infection at the chorio-decidual interface in the lower uterine segment. This model could provide important mechanistic observations that cannot be determined in lower mammalian models of preterm birth, due to known differences in placentation and parturition (onset of labor).
The central hypothesis is that infection with group B streptococcus (GBS) at the chorio-decidual interface in the lower uterine segment will result in an inflammatory response that stimulates premature myometrial contractions, IAI, and premature delivery. We propose to establish a model of preterm labor that more closely replicates the natural history of human preterm labor than prior animal models, by mimicking an ascending lower genital tract infection in a rhesus monkey. The new model will introduce GBS at the chorio-decidual interface in the lower uterine segment of a pregnant dam, monitor maternal and fetal physiological responses before and during infection, and sequentially sample the maternal, fetal, and amniotic fluid compartments.
We believe these initial experiments will lay the foundation for our longer term objectives which include:
- to elucidate the pathophysiologic mechanisms of ascending infection-induced preterm labor;
- to establish the cellular and molecular links among intrauterine infection and preterm labor using genomics; and
- to develop non-invasive diagnostic strategies for detecting infection-associated preterm labor.
Funding Source: March of Dimes
Contact: Kristina M Adams Waldorf
Ends 3/14/12
Top of Page
Global Alliance for the Prevention of Prematurity and Stillbirth
Michael Gravett, MD
Globally, preterm births and stillbirths represent major public health challenges. It is estimated that there are 14 million preterm births globally each year. Premature birth is the leading cause of death in the neonatal period, responsible for more than a million deaths globally each year. In addition, an estimated 3.2 million stillbirths occur each year worldwide.
The Global Alliance for the Prevention of Prematurity and Stillbirth (GAPPS) is an alliance of internationally renowned core investigators, under the direction of Craig E. Rubens, MD. PhD, intended to bridge basic science, epidemiology, and applied public health research to accelerate discovery and translational science for interventions to improve maternal and neonatal health.
Funding Source:
Bill and Melinda Gates Foundation, Children’s Hospital Regional Medical Center
Contact: Michael G. Gravett, MD
Ends 5/30/09
Top of Page
back to Research
|
