Terrie E. Inder - US grants

DESCRIPTION (provided by applicant): Advances in prenatal and neonatal care have significantly improved survival of the prematurely born infant, particularly the most immature. However, as these children approach school age, it is recognized that up to 50% face neurobehavioral challenges. The nature of the cerebral injury that underlies all of these neurobehavioral deficits is not yet fully understood, but common patterns of injury are found in the cerebral white matter including hemorrhage and cystic infarction known as periventricular leukomalacia (PVL). It is also increasingly recognized that there is primary or secondary injury in the cortical and deep gray matter and the hippocampus, which may relate to subsequent intellectual impairments. It is critical that we gain insight into how particular neonatal practices, such as respiratory support, may alter the nature and the severity of cerebral injury in these vulnerable infants. In this study we propose to investigate the nature of cerebral injury in a prematurely born primate model (Papio sp) developed as a model of bronchopulmonary dysplasia, utilizing both magnetic resonance imaging (MR) and histopathology. Our hypothesis is that the prematurely born baboon (Papio sp) will display a pattern of cerebral injury, evident on MR imaging and histopathology, similar to that found in the prematurely born human infant. This pattern of injury will vary in relation to the nature of postnatal therapies, particularly randomized ventilatory strategies. For each of the specific aims the methodologies are identical and will utilize both state-of-the-art advanced MR imaging techniques and histopathological studies in all subjects. The advanced MR imaging techniques will include conventional MR imaging, quantitative volumetric 3-dimensional imaging and diffusion tensor imaging with collaborations between three-world class research MR sites (Washington University, Melbourne University and Harvard Medical School). The histopathology will include immuno-histochemistry including structural classification, cellular characteristics - neuronal and glial, and growth factor and biochemical development. Although histopathological techniques will be the cornerstone of defining the nature and severity of the cerebral injury, the MR studies will allow a direct comparison between this model and the human infant in whom identical protocols of advanced MR studies in vivo are being currently undertaken in our program. These studies may provide insight into the relationship of neonatal respiratory care to risk of cerebral injury, and thus direct us to the safest modes of ventilatory support for the immature brain.

[unreadable] DESCRIPTION (provided by applicant): Preterm birth is a major public-health issue because of its increasing incidence combined with the frequent occurrence of subsequent behavioral, neurological, and psychiatric challenges faced by surviving infants. Approximately 10-15% of very preterm children (born < 30 weeks gestational age) develop cerebral palsy, and 30 - 60% of very preterm children experience cognitive impairments. These impairments include visual-motor problems, attentional difficulties, impaired memory, delayed acquisition of language, executive dysfunction, learning disabilities, poor social skills, and higher rates of social withdrawal, anxiety and depression. In addition, an increased prevalence of developmental disorders such as attention deficit/hyperactivity disorder, autism and schizophrenia, has been described in the preterm population. A greater understanding of the mechanisms leading to neurobehavioral impairments in preterm children is an important step in developing strategies for improving clinical outcomes. We have a unique, large cohort of 229 preterm infants (<30 weeks gestation or <1250g) for whom we have developed an extensive perinatal database and obtained advanced magnetic resonance (MR) images at term equivalent. Evaluation of these data has led to novel insights into the nature of the cerebral lesion associated with preterm birth. Importantly, we have maintained ongoing contact with 97% of this cohort during the course of longitudinal neuropsychological follow up. This population now offers a rare opportunity for longitudinal evaluation of the mechanisms of neurobehavioral impairment in association with modern, advanced MR imaging methods. We propose to apply state-of-the-art MR imaging methods to this cohort at 6 years of age in conjunction with neuropsychological evaluation. The MR data will allow us to study the evolution of structural changes in the brain from term equivalent into childhood in both the preterm and term born infants. The techniques will include surface based morphometry (SBM), brain volume measurements (volumetry), and diffusion tensor imaging (DTI). The MR approaches will provide both macroscopic (volumes and SBM) and microscopic (DTI) measures of cerebral development that address different aspects of brain structure and maturation. These will be related to the longitudinal social and neuropsychological evaluations to investigate the relationship of MR measures to neurobehavioral impairments. The longitudinal design will allow us to study both structural abnormalities and compensatory changes over childhood in response to early brain injury. These data will likely provide new understanding of neural recovery and strategies for improving outcomes in preterm infants. PUBLIC HEALTH RELEVANCE: This study is designed to use magnetic resonance (MR) imaging to improve our understanding of the brain injury sustained by prematurely-born infants and how the brain subsequently develops over childhood. The longitudinal design, using both advanced MR imaging and psychological testing, will allow us to study both structural abnormalities and positive adaptive changes over childhood in response to early brain injury. This will assist us in understanding how to reduce the global and specific disabilities that these vulnerable children later face. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Preterm birth is a major public-health issue because of its increasing incidence combined with the frequent occurrence of subsequent behavioral, neurological, and psychiatric challenges faced by surviving infants. Approximately 10-15% of very preterm children (born < 30 weeks gestational age) develop cerebral palsy, and 30 - 60% of very preterm children experience cognitive impairments. These impairments include visual-motor problems, attentional difficulties, impaired memory, delayed acquisition of language, executive dysfunction, learning disabilities, poor social skills, and higher rates of social withdrawal, anxiety and depression. In addition, an increased prevalence of developmental disorders such as attention deficit/hyperactivity disorder, autism and schizophrenia, has been described in the preterm population. These adverse outcomes are related to white matter (WM) and grey matter (GM) injury sustained during the neonatal period and its effects on subsequent brain development. We seek to develop imaging biomarkers, measurable during infancy, that provide sensitivity and specificity in identifying infants at risk for poor neurodevelopmental outcome. The biomarkers will consist of the following magnetic resonance (MR) imaging measures: 1) conventional T1- and T2-weighted images, 2) volumetry (volumes for cortical GM, deep nuclear GM, myelinated WM, unmyelinated WM, and cerebrospinal fluid), 3) diffusion tensor imaging (apparent diffusion coefficient, relative anisotropy, axial and radial diffusivity), and 4) surface-based morphometry (integrated folding index, average sulcal depth, cortical surface area, percentage of buried cortex). The main cohort of this study will consist of 120 very preterm infants born < 30 weeks gestational age. They will undergo MR studies soon after birth, at 30 weeks postmenstrual age (PMA), 34 weeks PMA, and term equivalent. Infants enrolled during Year 1 (n = 30) will also be imaged at age 4 years. The MR indices listed above will be compared with MR data from healthy control subjects and clinical outcome data obtained at term equivalent and 2 and 4 years of age. The proposed studies are designed to engender a deeper understanding of the nature and timing of cerebral injury, laying the groundwork for the development of neuroprotective strategies and improving clinical practices. The longitudinal design will allow us to study both structural abnormalities and compensatory changes in response to injury. Identification during the newborn period of infants at high risk for poor developmental outcome will allow early targeting of therapy services to these infants. If successful, the proposed studies will lead to improved outcomes for prematurely-born infants. Project Narrative: This study is designed to use magnetic resonance imaging to improve our understanding of the brain injury sustained by prematurely-born infants. This understanding has the potential to improve clinical practices and assist with the development of medications to reduce injury in these babies, ultimately reducing disabilities. It will also help identify those infants who are at high risk for developing cerebral palsy or mental retardation so they can be provided early access to therapy services.

Washington University in St. Louis is an internationally known neuroscience research institution. The WUIDDRC will build on this, making existing, sophisticated methods more readily accessible to Center investigators. The University also has fundamental gaps in its research infrastructure for intellectual and developmental disabilities, and the WUIDDRC will rectify those shortcomings. Finally, the WUIDDRC will promote a collaborative, interdisciplinary environment that will accelerate research productivity in intellectual and developmental disabilities. The primary objective of the Administrative Core is to support the Center's purpose and the attainment of these objectives by two key functions - scientific leadership and Administrative supportjo ensure excellence in Core services. The first and most important is the provision of scientific leadership facilitated by the spirited exchange of ideas. The second is the management, co-ordination and administration of all Center activities. The core will support a range of leadership and Administrative functions including: 1) supporting the work of Core Directors;2) managing the financial reporting;3) assisting with staffing within Cores;4) coordinating communication within the Center and with the community;5) recruitment of new WUIDDRC investigative members;6) managing the Center website;7) coordinating research forums;and 8) disseminating research information throughout the Center and the greater community. All investigators within the Center will have access to the services of the Administrative Core. The scientific leadership of the Center is critical to the success of the mission of the Center. The Director, Dr. Terrie Inder, is responsible for steering the scientific course of the Center, making all budgetary decisions and coordinating WUIDDRC activities. The leadership of the Center was carefully thought through at the inception of the center. Dr. Inder was selected as the leader for the center based on the recognition of her strength as a researcher and leader by the senior members of the research community. She is dedicated to creating an environment of scientific excellence with support for facilities and personnel. She has developed strong working relationships with all the current Chairs and the Dean of the Medical School, who respect her skills and leadership. They have demonstrated their confidence in her by pledging nearly $2 million in support over the first 5 years of the new center. Dr. Inder reports directly to the Dean of the Washington University School of Medicine in matters regarding the IDDRC. She was recently promoted to Full Professor at Washington University, effective July 1st '2010. Following the first WUIDDRC submission. Dr. Inder elected to appoint a panel of Associate Directors to assist with the scientific direction of the Center and to provide broader experience in institutional leadership. She selected each Associate Director primarily on the basis of his/her research and clinical expertise to fulfill a cleariy defined role in the leadership of the Center (Table A.I). This directorship model is functioning successfully in other Research Centers within Washington University, such as the Alzheimer's Disease Research Center. Each Associate Director has been assigned leadership areas related to his/her scientific expertise. The Associate Directors review the short-term objectives and priorities of the Center with the Director via meetings or conference call for an hour every two weeks. All Associate Directors have invested in this commitment with regular meetings having commenced in December 2009. Issues to be covered at these meetings include co-ordination of seminars for the Center;challenges related to utilization and/or investigator feedback for core services;budgetary issues;and community liaison. The long-term objectives and priorities will be reviewed every six months in conjunction with the Center Management Committee (CMC). These objectives include the scientific priorities of the WUIDDRC and their attainment. Items to be covered at these meetings include review of the research productivity of the Center;methods and success in attracting new investigators;budgetary goals and outcomes;use of core services;feedback on quality from investigators;community liaison;and the integration of the WUIDDRC with other Center/Cores/Departmental services within Washington University.

DESCRIPTION (Provided by Applicant): The goal of the Washington University Intellectual and Developmental Disabilities Research Center (WUIDDRC) is to promote cutting-edge Innovation to understand and treat intellectual and developmental disabilities. WUIDDRC would provide core resources for 44 outstanding investigators conducting 62 projects related to intellectual and developmental disabilities. WUIDDRC has four main goals: 1. Promote research on developmental disabilities, through new research opportunities, excellence in research facilities, intellectual stimulation, and Interdisciplinary collaborations. WUIDDRC will focus on investigators studying three complementary but fundamentally interrelated research theme areas: cerebral connectivity, genetics, and environmental influences. 2. Provide efficient, cost-effective, state-of-the-art services and facilities to enhance the quality and productivity of WUIDDRC investigators through five cores: Administration, Biostatistics and Informatics, Human Clinical Studies, Brain Imaging, and Animal Model Studies. 3. Create a strong and efficient infrastructure to support research activities related to developmental disabilities. WUIDDRC will attract established and new investigators to add new knowledge and develop innovations impacting IDD. The strategy is to create opportunities for novel collaboration in a large pool of leading research scientists. 4. Build a mechanism for effective, regular, and frequent communication and coordination among WUIDDRC investigators, researchers in other organizations, clinical providers for children with developmental disabilities, and the local community. Washington University in St. Louis has a long record of excellence in neuroscience. But it has gaps in infrastructure to integrate and coordinate research targeted to intellectual and developmental disabilities. WUIDDRC would make existing, sophisticated, and novel approaches readily accessible to its investigators to close these gaps. A practical outcome is to focus local talent on a pressing health problem that offers considerable potential to advance understanding of human brain development. WUIDDRC will stimulate advances by creating a collaborative, interdisciplinary environment that will accelerate research to directly impact children with intellectual and developmental disabilities.

DESCRIPTION (provided by applicant): Proliferative retinopathy (PR), which includes retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (DR), represent a leading cause of blindness in both children and working-age adults. Although PR is characterized by pathological retinal vascular overproliferation or neovascularization, therapies aimed at specifically inhibiting production of vascular endothelial growth factor (VEGF) have failed to consistently improve clinical outcomes. This observation clearly indicates that additional molecular factors/pathways contribute to pathological retinal neovascularization in PR and may thus be viable therapeutic targets. In this regard, we became intrigued by our preliminary finding that strong indoleamine-2,3-dioxygenase (IDO) expression is present in the vitreous of patients with DR as well as in the endothelium of retinal neovessels from mouse pups undergoing oxygen-induced retinopathy (OIR). Further, in in vitro experiments, we found that up-regulation of IDO endows the vascular endothelial cells (ECs) with enhanced capacity for proliferation, migration and tube formation independently of VEGF. In light of these novel findings we hypothesize that that endothelial IDO possesses pro-angiogenic activity, and that targeted inhibition of this enzyme will block the pathological retinal angiogenesis/neovascularization in PR. To test this hypothesis, we will use a number of unique approaches, which include a stable IDO-overexpressing retinal vascular EC line and the Sleeping- Beauty (SB)-based nonviral gene integrating strategy capable of long-lasting human IDO (hIDO) transgene expression within retinal ECs in vivo. In Specific Aim 1, we will evaluate the pro-angiogenic activity of endothelial IDO in vitro and in vivo, with a focus on the the molecular mechanism(s) behind IDO-induced phenotypic switching of retinal ECs from a normal to a pro-angiogenic state. In Specific Aim 2, we will examine the therapeutic potential of pharmacological inhibition of retinal endothelial IDO in the prevention of experimental PR. In these studies, we seek to achieve the therapeutic goal using selective IDO inhibitor 1-metheyl-DL-tryptophan (1-mT), a small molecular chemical (molecular weight 218) that can be orally or intraperitoneally administered and is currently used in anti-cancer clinical trials with satisfactory safety profile. Taken together, this proposal addresses a critical scientific gap in the treatment of PR, and if proven effective, may be fast-tracked to a phase 1 clinical trial.

PROJECT SUMMARY/ABSTRACT Every year in the United States about 30% of the 60,000 infants born extremely premature (<30 weeks gestational age and <1000 g birth-weight [ELGA]) develop intraventricular hemorrhage (IVH). IVH is associated with high risk for cerebral palsy and significant intellectual disability, causing lifelong implications for affected children and their families and considerable economic burden. IVH is caused by the rupture of the fragile capillaries in the germinal matrix which cannot withstand fluctuations in cerebral blood flow (CBF). In >90% of cases, these injuries occur during the first three postnatal days during a period of cardiorespiratory instability that has a direct effect on CBF, which results in periods of cerebral hypo- and hyper-perfusion. Current management strategies, such as changes in ventilation or inotrope support, are blind to the impact on CBF. Improved bedside technologies to continuously monitor CBF are urgently needed to allow the clinician to make informed decisions, to optimize current strategies and foster the development of new interventions to reduce the incidence of IVH in ELGA infants and to improve developmental outcomes. Building on our ten years of success measuring infants with non-invasive bedside optical methods, we propose to design and build a novel fast, three-wavelength, five-distances diffuse correlation spectroscopy (DCS) system, optimized for continuous monitoring of CBFi in ELGA infants. DCS directly quantifies an index of cerebral blood flow (CBFi) by measuring the temporal fluctuations of light generated by the dynamic scattering of moving red blood cells. To be of use in the ELGA infant, this bedside monitor needs to be safe, continuous, precise, reliable, quantitative and gently wearable. These pre-requisites will be met by designing an optical sensor which can be gently applied to the ELGA infant. The device will adopt a novel multi-distance, multi-wavelength method to assess tissue scattering and absorption coefficients, which are needed in combination with autocorrelation decay rates to correctly quantify CBFi. The novel DCS system will be initially tested by the Massachusetts General Hospital (MGH) team in phantoms to verify performance and demonstrate precision and accuracy of flow estimates. The system will then be tested in more mature, stable premature infants at the Brigham and Women's Hospital (BWH) NICU to evaluate feasibility of long measurements, compatibility with the NICU environment, skin integrity after long monitoring periods, and in-vivo algorithm validation. Finally, the device will be used in 100 ELGA infants during the first 72 hours of life to test our hypothesis that DCS-measured CBFi fluctuations and pressure-passive events correlate with incidence and severity of IVH. Our goal is to provide a much-needed cerebral blood flow monitor to guide individualized treatment with the goal of reducing the risk of IVH and improving long term neurodevelopmental outcomes among ELGA infants. This study in 100 ELGA infants will set the stage for a larger trial alongside commercialization.