2012 — 2016 |
Burd, Irina |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Il-1beta Regulation of Perinatal Brain Injury @ Johns Hopkins University
DESCRIPTION (provided by applicant): 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.
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0.955 |
2019 — 2021 |
Burd, Irina Klein, Sabra L. (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Il-1? Regulation of Zika-Mediated Adverse Perinatal Outcomes @ Johns Hopkins University
SUMMARY Zika virus (ZIKV) infection of pregnant females results in congenital infection of offspring and long-term developmental birth defects. Using an immunocompetent mouse model that we developed (published in Nature Communications), we have shown that intrauterine infection with either African, American, or Asian strains of ZIKV during early, but not late, pregnancy causes infection of the placenta and fetuses, placental inflammation, neonatal cortical thinning, and short-term neurologic deficits in offspring. More recently, we have demonstrated that placental IL-1? concentrations are elevated in ZIKV-infected dams, and we can reverse the ZIKV-associated short-term neurobehavioral sequelae in offspring by blocking IL-1 receptor signaling during the infection. We hypothesize that placental inflammation following intrauterine ZIKV infection causes perinatal neurological injury, which can then be reversed by targeting maternal IL-1? signaling. While most ZIKV interventions focus on antivirals and vaccines to limit perinatal ZIKV infection, to date no studies have considered the role of maternal and placental inflammation as a mechanism mediating long-term adverse perinatal outcomes following ZIKV infection. Specific Aim 1 will assess the mechanisms mediating elevated IL- 1? signaling in the placenta at different gestational ages following ZIKV infection, the long-term downstream effects of the placental immunopathology and placental IL-1? signaling, and whether these effects are sex- specific. In particular, Aim 1 will determine how placental inflammasome activation, IL-1? release, or engagement of the IL-1 receptor lead to adverse perinatal outcomes. Specific Aim 2 will examine the importance of maternal as opposed to fetal IL-1? signaling in the pathogenesis of perinatal brain injury following ZIKV infection. Using embryo transfer of IL-1? signaling deficient and wild type mouse strains, Aim 2 will assess whether IL-1? activity of maternal origin is critical for sex-specific fetal brain injury. Our novel translational research proposal, utilizing a ZIKV model that we developed, will have a significant impact on perinatal medicine as it will lead to a better understanding of the role of placental inflammation in the pathogenesis of fetal congenital diseases caused by infection or other inflammatory states during pregnancy.
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1 |
2019 — 2020 |
Burd, Irina Mathad, Jyoti S |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Placental Determits of Neonatal Immune Function in Maternal Hiv Infection @ Weill Medical Coll of Cornell Univ
ABSTRACT: HIV-exposed but uninfected (HEU) infants are twice as likely to die as HIV-unexposed and uninfected infants (HUU), mainly from other infectious diseases. There is an urgent need to understand how maternal HIV infection?whether controlled or not? impacts the development of the neonatal immune system. With this information, we can develop algorithms to prevent infectious diseases in HEU that account for their functional immune deficits. We hypothesize that maternal HIV infection results in inflammation of the placenta, decreased maternal-to- child transfer of antibodies, and differential programming of the neonatal immune system that impairs the immune response to vaccines. To test this hypothesis, we will integrate clinical data with immunologic data we will obtain from maternal, placenta and neonatal samples that were collected as part of an NIH-funded R01 study we have been conducting in India since 2014. We enrolled a unique, well-defined cohort of maternal- infant pairs with and without HIV and followed them longitudinally through pregnancy and the first year postpartum. We propose to capitalize on these stored samples to address the following aims: Aim 1. Compare the Treg/CD8+ T cell ratio in maternal blood, placenta, and cord blood samples by maternal HIV status and viral load. This aim will establish the relationship between immune cells and cytokines in maternal blood, placenta and cord blood samples, using flow cytometry, immunecard technology and immunohistochemical staining. Understanding how maternal and placental immunology relate to neonatal immune development may help us predict which infants will have impaired immune responses to pathogens. Aim 2. Determine the effect of placental immune function on infants? humoral and cellular immunity. This aim will (1) identify how HIV decreases the transplacental transfer of antibodies to key respiratory pathogens involved in HEU infant mortality, including S. pneumoniae, H. influenzae, and influenza virus; and (2) determine if placental inflammation impacts the longevity of the infant?s immune response to BCG vaccine. Using these data, we can develop screening tests to predict which neonates will have the greatest immune compromise at birth. Studying the role of the placenta in the development of the neonatal immune system may also reveal key differences between HEU and HUU infants that will allow us to optimize care for this vulnerable population.
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0.933 |
2021 |
Burd, Irina Fallin, M Daniele [⬀] Kaufman, Joan R. |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
7/24 Healthy Brain and Child Development National Consortium @ Johns Hopkins University
HBCD-NC Project Summary/Abstract Neurodevelopmental processes are shaped by dynamic interactions between genes and environments. Maladaptive experiences early in life can alter developmental trajectories, leading to harmful and enduring developmental sequelae. Pre- and postnatal hazards include maternal substance exposure, toxicant exposures in pregnancy and early life, maternal health conditions, parental psychopathology, maltreatment, structural racism, and excessive stress. To elucidate how various environmental hazards impact child development, it is imperative that a normative template of developmental trajectories over the first 10 years of life be established based on a sufficiently large and demographically diverse sample of the US population. To accomplish this, the Healthy Brain and Child Development National Consortium (HBCD-NC) has been formed to deploy a harmonized, optimized, and innovative set of neuroimaging (MRI, EEG) measures complemented by an extensive battery of behavioral, physiological, and psychological tools, and biospecimens to understand neurodevelopmental trajectories in a sample of 7,500 mothers and infants enrolled at 24 sites across the United States (US). The HBCD-NC will carry out a common research protocol under direction of the HBCD-NC Administrative Core (HCAC) and will assemble and distribute a comprehensive and well-curated research dataset to the scientific community at large under the direction of the HBCD-NC Data Coordinating Center (HDCC). The overarching goal of the HBCD-NC is to create a comprehensive, harmonized, and high- dimensional dataset that will characterize typical neurodevelopmental trajectories in US children and that will assess how biological and environmental exposures affect those trajectories. A special emphasis will be placed on understanding the impact of pre- and postnatal exposure to opioids, marijuana, alcohol, tobacco and/or other substances. To address these broad objectives, the sample of women enrolled will include: 1) a racially, ethnically, and socioeconomically diverse cohort that is representative of the US population; 2) pregnant woman with use of targeted substances (opioids, marijuana, alcohol, tobacco); and 3) demographically and behaviorally similar women without substance use in pregnancy to enable valid causal inferences. In addition, the HBCD-NC will identify key developmental windows during which both harmful and protective environments have the most influence on later neurodevelopmental outcomes. The large, multi-modal, longitudinal, and generalizable dataset that will be produced for the first time by this study will provide novel insights into child development using state- of-the-art methods. The HBCD-NC study will inform public policy to improve the health and development of children across the nation.
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1 |
2021 |
Burd, Irina Ensign, Laura |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Nanomedicine Approaches For Prevention of Inflammation-Induced Preterm Birth @ Johns Hopkins University
Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not accounting for the lifelong impact of developmental and cognitive impairments. Here, we focus on the most common cause of PTB, inflammation. Maternal inflammation triggers a pro-inflammatory cytokine response that can also lead to fetal inflammatory response syndrome and perinatal brain injury. Brain injury leads to a spectrum of adverse neurobehavioral outcomes, including cerebral palsy, autism, schizophrenia, and cognitive delay among others. The only approved drug for prevention of PTB is the synthetic progestin hydroxyprogesterone caproate (OHPC) dosed systemically as weekly injections in women with a singleton pregnancy with a history of singleton spontaneous PTB, and a recently failed confirmatory study has led to calls for the FDA to withdraw the drug from the market. For women that are already in preterm labor, off-label tocolytics (anti-contraction medications) may be given to slow uterine contractions, but this typically only delays birth for a few days. New, effective treatments for preventing PTB are desperately needed. Further, the vaginal route of administration is underexplored but highly promising; vaginally absorbed drug is preferentially transported to the uterus. We have demonstrated that by increasing mucosal drug penetration and eliminating hypertonic excipients that cause local toxicity, increased drug delivery to target reproductive tissues can be achieved. In the setting of intrauterine inflammation, we have observed that combining vaginal progesterone (P4) with drugs that favor non-laboring states of P4 receptor and gene expression, such as histone deacetylase inhibitors (HDACi), provides a significant increase in dams that go on to deliver live pups. In contrast, dosing the same drug combination systemically or injecting the approved product OHPC had no therapeutic effect. Analysis of gene expression changes suggest that quiescing myometrial activity was key, and we have confirmed that the myometrial tissue levels of P4 and HDACi measured after vaginal combination delivery in mice were also the most effective in preventing human myometrial cell contractility. Importantly, preliminary neurobehavioral analysis of pups born after exposure to intrauterine inflammation followed by vaginal P4/HDACi suggests that development occurred similar to pups that had not been exposed to intrauterine inflammation. Herein, we propose studies that build from exciting preliminary data using nanomedicine to address fundamental questions regarding route of administration, pharmacokinetics, as well as validating existing drug classes that may be reformulated and repurposed for improved targeting to the female reproductive tract. If these preclinical studies progress as expected, we will have identified novel, effective methods for prevention of inflammation-induced PTB that also support fetal and neonatal immunological programming and development.
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1 |