Project Details
Description
ABSTRACT
The World Health Organization estimates that the annual rate of preterm birth (PTB) is greater than 10% in
most countries. Premature birth is the leading cause of mortality in the first year of life and is associated with
morbidity that includes life-long cognitive challenges. Acute and long-term care costs associated with preterm
birth have far reaching effects on families and are enormously expensive for society. Although PTB is a
multifactorial disorder, the single most common cause is inflammation. Sadly, there is currently no Food and
Drug Administration approved drug for the prevention of PTB. Efforts to develop drug therapy to delay or
prevent PTB have been hampered by the low efficacy and potential teratogenicity of candidate drugs. Several
years ago, we made the fortuitous discovery that the widely used pharmaceutical excipient, N,N-
dimethylacetamide (DMA), prevents PTB and rescues pups from spontaneous abortion in our mouse model.
Further studies in our laboratory revealed that DMA suppresses nuclear translocation and activation of nuclear
factor kappa B (NF-B), a transcription factor that regulates immune cell-mediated inflammation. In addition, we
have shown that DMA attenuates cytokine secretion from cultured human trophoblasts and from human placental
explants. Recently, our laboratory has teamed up with our collaborator’s to develop a vaginal (pv) self-
nanoemulsifying drug delivery system (SNEDDS), which takes advantage of the first uterine/cervix pass effect to
deliver drugs introduced into the vaginal cavity directly to the cervix and uterus, thereby minimizing risk of
systemic toxicity and teratogenicity. The major goal of the parent grant is to test the hypothesis that our vaginal
(pv) DMA loaded SNEDDS will deliver efficacious concentrations of DMA directly to cervix target tissue to
prevent PTB without causing teratogenic effects. The Cellcyte X live cell analyzer provided by this grant
supplement will allow us to investigate how DMA loaded SNEDDS and neat DMA affect the function of
cervical macrophages in the pathogenesis of inflammation driven preterm birth. The specific aims of this
grant supplement are 1) to test the hypothesis that DMA promotes M1 to M2 macrophage phenotype switching
and 2) to test the effect of DMA on macrophage phagocytic function. The Cellcyte X live cell analyzer will be
housed in the PD/PI’s laboratory and fits into a standard cell culture incubator. Young investigators, who come
from under-resourced parts of the world where rates of PTB are high, will use it routinely, as they develop into
well-trained biomedical scientists. This proposal will provide important information that will sharpen our
understanding of the effect of two different DMA formulations on cervical macrophages that play a key role in
PTB and will help refine the development of the ideal DMA formulation for the prevention of PTB.
Status | Active |
---|---|
Effective start/end date | 5/11/22 → 4/30/24 |
Funding
- National Institute of General Medical Sciences: $164,000.00
- National Institute of General Medical Sciences: $164,000.00
- National Institute of General Medical Sciences: $67,125.00
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