Michael O'Shea - US grants

This SQUID-based sample magnetometer will perform fast, precise measurements of the magnetic properties of materials over a broad range of temperatures and applied magnetic fields. It has a complete and sophisticated computer operating system for control and analysis and allows for total automation. The proposed instrument exceeds current equipment ability in sensitivity, temperature control, and computer control. The system will be used by four faculty members of the Physics and Chemistry departments for fundamental materials research, and will aid in training of undergraduates and graduate students (20), and postdocs (3). The SQUID magnetometer is a central measurement and characterization apparatus for several projects: measurement of magnetic properties of ultrafine parcticles prepared via novel synthetic techniques having unique compositions and structures; studies of storage and relaxation processes of photoexcited charge carriers in II-VI mixed crystals and related critical phenomena; studies of magnetic anisotropy and interface exchange in multilayers of rare-earth metals and transition metals and their oxides and studies of critical phenomena in these systems; and measurements of organic ferromagnets.//

DESCRIPTION: (Provided by Applicant) Broad, long-term objective: The broad goal of the Cooperative Multicenter Neonatal Research Network is to contribute to the identification of therapies to reduce infant mortality and morbidity . Specific aim: The specific aims of Wake Forest University School of Medicine (WFUSM) as a participant in the Neonatal Research Network is to enroll patients into clinical trials and offer expertise to the Steering Committee?s efforts to design trials that are clinically relevant and methodically rigorous. These specific aims will be achieved by recruiting subjects from the two neonatal intensive nurseries directed by WFUSM?s Division of Neonatology. These two nurseries contain over 90% of the level ill neonatal intensive care unit beds in a 19-county region in northwest North Carolina. Each year in this region there are approximately 20,000 births, including 1400 who are admitted to the WFUSM neonatal intensive care units, and 270 who are very low birth weight. An important attribute of WFUSM is that it is a regional perinatal and neonatal center which provides care primarily for a geographically-based sample of neonates, with sociodemographic characteristics that resemble those of the US population. Research protocols that include outcomes identifiable after discharge from the hospital will be facilitated by WFUSM?s Infant Follow-up Program, in which developmental and follow-up is provided to all very low birth weight infants discharged from WFUSM?s two neonatal intensive care units. Since 1977, the follow-up rate for very low birth weight infants, through one year corrected age, has always exceeded 80%. WFUSM?s Maternal-Fetal Medicine Section will facilitate clinical protocols requiring prenatal interventions or assessments. The WFUSM Maternal-Fetal Medicine Section is the only provider of tertiary level obstetric services in the geographic region served by the two neonatal intensive care units at WFUSM, and is a site in the NIH-sponsored Maternal Fetal Medicine Multicenter Research Network. The institutional principal investigator for the Neonatal Research Network at WFUSM has a Masters degree in Public Health (Epidemiology) and fourteen years of experience in clinical outcomes research, emphasizing infant developmental outcome. Additional institutional resources include an NIH-sponsored General Clinical Research Center, an outstanding Department of Public Health Sciences, a Genomics center, a full range of pediatric subspecialists, state-ofthe art neonatal and obstetric facilities, and excellent support staff of respiratory therapists, nurses, and research nurses.

DESCRIPTION (provided by applicant): The Society for Pediatric and Perinatal Epidemiologic Research is an open-membership society comprised of researchers from a variety of backgrounds, all of whom share an interest in the epidemiology of normal and abnormal growth and development of children, from their conception through adolescence. The purpose of the Society is to foster research in this discipline by encouraging communication and exchange of ideas and research results between established investigators as well as between new and established investigators. In its eleven years of existence, it has met these goals successfully, and its annual meeting has become the primary congregating point of researchers in the fields of perinatal and pediatric epidemiology. Three popular features of the meeting are the Student Prize Paper, the International Prize Paper and the Keynote Address. The Society currently funds 100% of the transportation, hotel and other costs of these awards. This request is for the NICHD to assist the Society by assuming funding of the transportation and hotel costs of these awards, thereby assuring the continued development of young investigators in pediatric and perinatal epidemiology into the next century.

Project Summary/Abstract The goal of the ECHO Consortium is to identify exposures and mechanisms that link the environment in early life to childhood development and health outcomes. This proposal commits to the ECHO Consortium numerous resources from the Extremely Low Gestation Age Newborn (ELGAN) Study. Since its initiation in 2001, the broad goal of the ELGAN Study is to evaluate the relationship between perinatal inflammation and neurodevelopmental impairments among individuals born extremely premature (i.e., before 28 weeks of gestation). In the proposed project we will build on the success of the ELGAN Study by adding new information about: 1) environment exposures, 2) neurodevelopmental outcomes of study participants at 15 and 18 years of age, and 3) placental epigenetic variation, a mechanism that could link inflammation early in life to neurodevelopmental impairments. In the first two years of the project (the UG3 phase) investigators from the ELGAN team will participate in the design of studies that can be implemented across the ECHO Consortium and in efforts to harmonize data across cohorts comprising the consortium. In the second year of the proposal, we will begin to evaluate members of the ELGAN cohort, as they reach 15 years of age, using standardized neurodevelopmental assessments and brain magnetic resonance imaging (MRI). We also will complete preliminary studies of relationships between prenatal environmental exposures, early life inflammation, and neurodevelopmental impairments, using extant data from the ELGAN cohort. In addition, we will complete analysis of epigenetic markers in placenta specimens collected around the time of the births of ELGAN Study participants. These data will be utilized in the last 5 years of the proposed project (the UH3 phase). If pre-specified milestones are met, the project will transition into the UH3 phase. Standardized neurodevelopmental assessments and brain magnetic resonance imaging (MRI) will be completed as study participants reach 15 years. As participants reach 18 years of age neurodevelopmental assessments will again be completed. At the assessment at 18 years we will obtain blood for study of epigenetic markers of activation of innate immunity, which we can then relate to our extant data about systemic inflammation early in life. Specific aims in the UH3 phase of the project are examine relationships between biomarkers of early life inflammation (extant data on neonatal systemic inflammation and new data on placenta epigenetics) and neurodevelopmental impairments through age 18 years. The over-arching hypothesis to be addressed is that prenatal exposures can initiate early life inflammation, thus increasing the risk of neurodevelopmental impairments. Innovative aspects of this project include its longitudinal perspective, consideration of placenta epigenetics as a mechanism linking prenatal exposures to childhood outcomes, and evaluation of a wide range of neurodevelopmental outcome. This research has the potential to inform the development of therapies targeting epigenetic processes to prevent or ameliorate cognitive disability, thereby improving the quality of life for 16,000 individuals who survive extremely premature birth each year in the United States.

Project Summary/Abstract This project addresses a critical gap in the understanding of sexual dimorphism in both infant and children?s health outcomes, where males are often at increased risk for disease. At the project?s core is the novel hypothesis that sexual epigenetic dimorphism in the placenta influence responses to perinatal stressors, and predict fetal growth restriction and neurodevelopment ND later in life. To address this, we use an ?-omics? and systems-wide approach to identify biomarkers of, and potential mechanisms for, adverse pregnancy outcomes (fetal growth restriction and neurodevelopmental impairment in the offspring) in an existing cohort of children born extremely prematurely (i.e., before 28 weeks of gestation). The ?omics approaches include DNA CpG methylomics, transcriptomics to assess messenger RNA), and proteomics. A tremendous strength of this proposal is the unique and extensively characterized US-based cohort recruited for the Extremely Low Gestation Age Newborn (ELGAN) Study. Since its initiation in 2001, the broad goal of the ELGAN Study has been to evaluate the relationship between perinatal inflammation and neurodevelopmental impairments among individuals born extremely premature. In the proposed project, we build on the success of the ELGAN Study by: 1) evaluating ?-omics? biomarkers in archived specimens of placenta and neonatal blood and 2) integrating these data with existing outcome data about fetal growth restriction and neurodevelopmental impairments in the ELGAN cohort. In the first three years of the project, DNA CpG methylation, mRNA, and selected proteins will be assayed in archived specimens of placenta and neonatal blood. Data analyses will begin in year 2, with an initial focus on establishing the relationships among placental and blood biomarkers and both fetal growth restriction as well as neurodevelopmental impairment. We also will study relationships between prenatal factors associated with adverse pregnancy outcomes (maternal obesity and placental bacteria) and placental and neonatal blood ?omics biomarkers. Furthermore, we will evaluate relationships between will placenta biomarkers and neonatal blood biomarkers. Innovative aspects of this project include its longitudinal perspective, consideration of placenta epigenetics as a mechanism linking prenatal exposures to childhood outcomes, and evaluation of CpG methylation marks in neonatal blood. With the potential for public health impact, this research may inform the development of therapies targeting epigenetic processes to prevent or ameliorate cognitive disability, thereby improving the quality of life for 16,000 individuals who survive extremely premature birth each year in the United States.

ABSTRACT This project addresses a critical gap in the understanding of potential links between race, the COVID-19 pandemic, and the well-being of children. We will evaluate these relationships by collaborating with other ECHO cohorts, thus increasing the geographical variation of our study sample. Our cohort, derived from the Extremely Low Gestational Age Newborn (ELGAN) study, provides the opportunity to evaluate relationships within subsets defined in terms of gestational age at birth. Given the high prevalence of early life adversities among individuals born extremely preterm, we anticipate finding increased vulnerability to the harmful effects of the COVID-19 pandemic. Although fewer children than adults have developed life-threatening infections due to COVID-19, the public health policies implemented to stop the spread of COVID-19 have disrupted children?s lives through economic depression, social distancing, and unprecedented educational disruptions. The shift to distance learning has changed children?s home, school, and social environments, but we know very little about the impact of these changes on children?s health and development. These disruptions may have stronger negative effects on historically underserved groups, including lower income families, as well as racial and ethnic minorities. This proposal seeks to evaluate the unintended psychosocial impacts of COVID-19 public health policies on children and families, and to examine if these effects are more prominent within lower income communities and communities of color. We examine if COVID-19 Health Policies impose more hardships on families within these groups, and if these hardships adversely affect their positive health development, as indexed by academic competence and well-being. By collaborating with cohorts comprised primarily of children born near or at term, we will also evaluate whether COVID-19 related stressors have greater impact on a particularly vulnerable group of children, i.e., those born extremely preterm. Further, we will examine if school practices related to distance learning and supportive social networks are also associated with child outcomes, independent of COVID-19 hardships. This project will identify processes by which public health policies influence families and will identify practices that promote children?s positive health development.

ABSTRACT This project addresses a critical gap in the understanding of the mechanisms that underlie susceptibility for neurodevelopmental disability and reduced brain volume as measured via magnetic resonance imaging (MRI) in children. At the project?s core is the novel hypothesis that the expression of critical inflammation and stress response pathways in the placenta is associated with neurodevelopmental disability and altered brain structure later in life. To address this, we use a combined approach focusing on the placenta-brain axis that incorporates placental ?-omics? data (gene expression), neonatal inflammatory biomarkers, neuroimaging measures, and neurodevelopmental disability data. This research focuses on cognitive and social impairment (including autism spectrum disorder; ASD) in an existing cohort of children born extremely prematurely (i.e., before 28 weeks? gestation). A strength of this proposal is the unique and extensively characterized Extremely Low Gestation Age Newborn (ELGAN) Study. Since its initiation in 2001, the broad goal of the ELGAN Study has been to evaluate the relationship between perinatal inflammation and neurodevelopmental impairments among individuals born extremely premature. In the proposed project, we build on the success of the ELGAN Study by evaluating placental gene expression biomarkers of inflammation and stress response and neonatal blood and integrating these data with existing MRI-derived outcomes and neurodevelopmental disability of cognitive and social impairment. In the first year of the project, gene expression of selected inflammation and stress response pathways will be assayed and examined using data from archived specimens of placenta. Data analyses will begin in year 1, with an initial focus on establishing the relationships among placenta and reductions in MRI-derived brain structure measurements and neurodevelopmental impairment at age 10 and 15. Furthermore, moving into year 2 we will evaluate whether inflammation in the neonate mediates the relationship between the placenta gene expression and MRI-derived brain outcomes and ND at age 10 and age 15. Innovative aspects of this project include its longitudinal perspective and evaluation of placental mRNA gene expression patterns relative to alterations in MRI-derived brain measurements to study the placenta-brain axis. With the potential for public health impact, this research promises to inform the development of expanded therapies targeting molecular processes early in pregnancy to guide future etiological studies for the prevention and intervention of neurodevelopmental disability. A long term goal of this research will be to improve the quality of life for the more than 16,000 individuals who survive extremely preterm birth each year in the United States.