In the United States, approximately 12% of all live births are delivered preterm. Intrauterine inflammation has been linked to a devastating spectrum of neurobehavioral disorders in these children, including cerebral palsy. Using a mouse model of intrauterine inflammation, from localized intrauterine lipopolysaccharide infusions, we have demonstrated an activation of excitotoxic pathways (neurotoxic pathways as a result of an excess of glutamate, or similar excitatory substances) in fetal brain. The observed """"""""propagated"""""""" disruption of fetal neuronal morphology and function may be a critical mechanism leading to long-term adverse neurological sequelae. Along with the fetal neuronal injury, we have also demonstrated a marked elevation of IL-1? in the fetal brain. IL-1? plays a key role in the pathogenesis of many neuroinflammatory disorders that involve excitotoxic pathways. Preliminary work from our laboratory has demonstrated that a maternally administered IL-1 receptor antagonist prior to intrauterine inflammation appears to prevent, in a brain-region specific manner, the fetal cortical neurotoxicity. Therefore, the objective of this study is to investigate mechanisms activated in the fetal brain in response to the intrauterine inflammation and the role of IL-1?, in order to pursue novel therapeutic strategies to prevent adverse neurological outcomes. Our overall hypothesis is that IL-1? mediates fetal cortical brain injury in intrauterine inflammation and is responsible for the long-term neurological changes. Elucidating the mechanisms by which fetal IL-1? production leads to neuronal death and long-term neurological outcomes, and whether this injury is sex-specific, will have important therapeutic implications. The training objective of this proposal is to achieve independence as a Maternal-Fetal Medicine physician- scientist with expertise in 1) fetal brain injury, 2) brain imaging for identification of fetal/neonatal brain injury and its response to therapeutics, and 3) assessment of neurobehavioral outcomes as translational tools in a mouse model of intrauterine inflammation. This applicant is particularly well suited to perform this research work due to her training as a Maternal-Fetal Medicine physician, her preliminary work involving the elucidation of mechanisms of fetal brain injury in the model of intrauterine inflammation, coupled with a mentoring relationship with an accomplished, extramurally funded, leading scientist whose expertise is in excitotoxicity and perinatal brain injury. Moreover, the environment at the applicant's institution is conducive for the development of this research and the institution is committed to her development as a tenure-track faculty member. This translational research will have a significant IMPACT on the field of perinatal medicine as it will not only uncover mechanisms involved in fetal brain injury with intrauterine inflammation but will also open new avenues in the field of fetal neurology.

Public Health Relevance

The purpose of this study is to investigate the mechanisms by which exposure to intrauterine inflammation leads to fetal brain injury. The training objective of this proposal is to achieve independence as a Maternal- Fetal Medicine physician-scientist with expertise in fetal brain injury. This translational research will have a significant IMPACT on the field of perinatal medicine as it will not only uncover mechanisms involved in fetal brain injury with intrauterine inflammation but will also open new avenues in the field of fetal neurology.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD073315-03
Application #
8657474
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Krotoski, Danuta
Project Start
2012-08-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$136,755
Indirect Cost
$10,130
Name
Johns Hopkins University
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Groff, Stephanie McKenney; Fallatah, Wareef; Yang, Samuel et al. (2017) Effect of Maternal Obesity on Maternal-Fetal Transfer of Preoperative Cefazolin at Cesarean Section. J Pediatr Pharmacol Ther 22:227-232
Lei, Jun; Xie, Li; Zhao, Hongxi et al. (2017) Maternal CD8+ T-cell depletion alleviates intrauterine inflammation-induced perinatal brain injury. Am J Reprod Immunol :
Lei, Jun; Paules, Cristina; Nigrini, Elisabeth et al. (2017) Umbilical Cord Blood NOS1 as a Potential Biomarker of Neonatal Encephalopathy. Front Pediatr 5:112
Sussan, Thomas E; Sudini, Kuladeep; Talbot Jr, C Conover et al. (2017) Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity. Sci Rep 7:40194
Johnson, C T; Burd, I; Raghunathan, R et al. (2016) Perinatal inflammation/infection and its association with correction of metabolic acidosis in hypoxic-ischemic encephalopathy. J Perinatol 36:448-52
Mainigi, Monica; Rosenzweig, Jason M; Lei, Jun et al. (2016) Peri-Implantation Hormonal Milieu: Elucidating Mechanisms of Adverse Neurodevelopmental Outcomes. Reprod Sci 23:785-94
Burd, I; Welling, J; Kannan, G et al. (2016) Excitotoxicity as a Common Mechanism for Fetal Neuronal Injury with Hypoxia and Intrauterine Inflammation. Adv Pharmacol 76:85-101
Tsimis, Michael E; Johnson, Clark T; Raghunathan, Radhika S et al. (2016) Risk factors for periventricular white matter injury in very low birthweight neonates. Am J Obstet Gynecol 214:380.e1-6
McKenney, Stephanie L; Mansouri, Fahad F; Everett, Allen D et al. (2016) Glial fibrillary acidic protein as a biomarker for brain injury in neonatal CHD. Cardiol Young 26:1282-9

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