[K23] Syphilis in pregnancy: placental histopathology and transcriptomic linkage to outcomes
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2030-06-30
Importo max: 167.383 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (T. pallidum), is an important cause of
stillbirth, preterm delivery, and neonatal death. In untreated syphilis in pregnancy, histopathologic findings of
necrotizing funisitis, proliferative vascular changes in the villi, acute or chronic villitis with a predominance of CD8
T cells, and increased villous macrophages of fetal origin (Hofbauer cells) are described. Little is known about
transcriptional dysregulation of immune cells in the dynamic immune microenvironment of the placental interface
along a spectrum of clinical syphilis disease and treatment. The objective of this proposal is to address
knowledge gaps by elucidating T pallidum-driven changes in the maternal-placental-fetal immune transcriptome,
linking maternal syphilis stage, treatment timing, treponemal burden, placental histopathology, and neonatal
outcomes. The central hypothesis is that adverse neonatal outcomes from syphilis, such as preterm birth,
correlate with placental pathology, high treponemal burden, and transcriptional dysregulation of CD8+ T cell and
Hofbauer cell populations in the placenta. In Aim 1, placental histopathologic phenotypes will be defined and
correlated with treponemal burden and neonatal outcomes along a spectrum of clinical disease and compared
to healthy controls. In Aim 2, differential placental gene transcriptional profiles will be linked to histopathologic
placental abnormalities, preterm delivery, and congenital syphilis. As Medical Director of Perinatal Infectious
Diseases at a maternity center with an annual delivery volume of over 12,000, Dr. Adhikari oversees the clinical
evaluation and management of approximately 150 patients with syphilis in pregnancy every year and has
collected robust preliminary clinical data. With the full support of UT Southwestern Medical Center, the Clinical
and Translational Science Award Program, the Department of Obstetrics and Gynecology, and the Green Center
for Reproductive Biology Sciences, as well as local and national mentors and expert advisors, Dr. Adhikari has
a rich environment in which to engage in individualized mentorship and career development, formal coursework
and hands-on learning to succeed. Research and training will be completed under the guidance of a robust
mentorship team, including experts in placental biology, infectious diseases in pregnancy, and genomics. This
K23 award will provide the training and resources needed for Dr. Adhikari to launch a successful career as an
independent investigator to better define the maternal-placental-fetal immune response to infection at the cellular
and molecular level and link these findings to adverse pregnancy outcomes such as preterm birth and congenital
infection.
Istituzione: UT SOUTHWESTERN MEDICAL CENTER
PI: Emily H Adhikari
Progetto: 5K23HD114892-02
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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