Gary J. Bassell, PhD, Emory University
Christina Gross, PhD, Emory University
Shannon Gourley, PhD, Emory University

The genetic and environmental etiologies of neurodevelopmental diseases, such as autism spectrum disorders, are highly diverse, and as a result, therapeutic strategies are lacking. The study of single-gene causes of these diseases has emerged as a promising research strategy that might further identify treatment approaches broadly applicable to larger groups of affected individuals. Recent evidence suggests that many genetic defects linked to autism converge onto a specific molecular complex within the cell – the phosphoinositide-3-kinase (PI3K)/mTOR signaling complex. For example, the most common inherited intellectual disability, fragile X syndrome (FXS), which is also frequently associated with autism, is characterized by dysfunction of the PI3K/mTOR complex. We hypothesize that reduction of PI3K/mTOR function might be a promising therapeutic strategy for FXS and other forms of autism. To test this hypothesis, we will follow a collaborative, two-pronged approach, which will characterize the effects of systemic and brain region-selective reduction of PI3K signaling on several molecular, cellular and cognitive functions in two mouse models of FXS. With this research project, we expect to generate new insight into brain region-selective functions of FMRP, and comprehensively test the suitability of PI3K reduction as a novel therapeutic strategy for FXS and possibly other developmental disabilities.

Notable outcomes: NIMH R21 award and NICHD U54 subcontract

Robert Craig Castellino, MD, Emory University and Children’s Healthcare of Atlanta
Erwin G. Van Meir, PhD, Emory University

BAI1 is a seven transmembrane G protein-coupled receptor (GPCR) specifically expressed in the brain thatour collaborators Erwin van Meir and Dan Zhuhave shown is silenced in glioblastoma multiforme (GBM) via epigenetic mechanisms. Their results demonstrate that BAI1 is anti-angiogenic and can potently suppress glioma growth, suggesting that restoration of BAI1 gene function in brain tumors might be of therapeutic value. Our preliminary data shows that BAI1 expression is significantly reduced in patient MBs, suggesting that BAI1 loss might facilitate MB formation. Furthermore, we have found that haploinsufficiency of Bai1accelerates MB tumorigenesis in a transgenic mouse model of MB, the first demonstration that reducedBai1 dosage promotes MB formation in vivo. In support of this observation, we detected enhanced expression of Gli2, a downstream indicator of active Sonic-hedgehog (Shh) signaling, and a thicker external granule layer (EGL) during early postnatal cerebellum development in Bai1knockout (KO) mice. Developmental biologists have previously shown that hyperplasia of the cerebellar EGL predisposes mice with activated Shh signaling to MB formation. Therefore, our studies link BAI1 with cerebellar development and neoplastic transformation. We hypothesize that BAI1 is a tumor suppressor in the cerebellum and that restoration of its expression willyield a novel therapeutic intervention for MB.

Notable outcomes: NINDS R01 award

Victor Faundez, MD, PhD, Emory University

Axon growth and maintenance requires a steady supply of organelles from neuronal cell bodies. Perturbations of trafficking and organelle transport mechanisms account for a diverse group of Mendelian disorders know as axonopathies. Among these axonopathies, those generated by mutations to genes encoding WASH complex subunits in humans cause hereditary spastic paraplegia, a late-onset distal axonopathy. Our proposal will test the hypothesis that the WASH complex regulates or is regulated by components of the BLOC pathway. We will test this hypothesis using powerful mouse genetic tools and motor function assays. Our goal is to identify genetic modifiers that could alter the outcome of hereditary spastic paraplegia.

Notable outcomes: NINDS R21 award

Shannon Gourley, PhD, Emory University
Kerry James Ressler, MD, PhD, Emory University

Work in the Gourley lab is driven by abundant epidemiological evidence that adolescence represents a period of increased vulnerability to the development of treatment-resistant depression. This outcome may relate to the effects of stress hormone exposure—a risk factor for depression at any age—on the prefrontal cortex, which reaches full structural maturity only at the end of adolescence. Based on this hypothesis, a major component of this proposal is to test whether genetic manipulation of two master regulators of postnatal cortical maturation, p190RhoGAP and BDNF, indeed are predictive of depressive-like behavior. Secondly, we will test the therapeutic-like properties of pharmacological agents that act on p190RhoGAP and BDNF function. There are no specialized pharmacological treatments for adolescent-onset depression; this proposal aims to better characterize the neurobiological consequences of stress hormone exposure on the structure and stability of prefrontal cortical neurons with the ultimate goal of developing specialized pharmacotherapies to treat adolescent-onset depression.

Notable outcomes: NIMH R01 award

Thomas G. Burns, PsyD, ABPP-CN, Emory University and Children’s Healthcare of Atlanta

Sports Related Concussion (SRC) has received a considerable amount of attention in recent years. This study will utilize neurocognitive testing in the acute (<7 days) and delayed (one month) phases of recovery to establish the severity and duration of post-concussive symptoms. Advanced neuroimaging procedures will also be utilized to evaluate cerebral blood flow, cerebrovascular reactivity, diffusion tesnsor imaging, fMRI, and morphometric analyses. This will be compared with traditional neuropsychological testing, which will include the ImPACT computerized concussion battery. These biomarkers will examined to determine (1) which factors reliably predicts the outcome of SRC, and to (2) provide insight into the mechanisms involved in SRC that will help to form prognostic judgments for determining which subjects diagnosed with SRC would benefit most from ongoing monitoring and (3) when does the physiological markers suggest the best time for to return to play when compared with neurocognitive testing.

Andrew Reisner, MD, Emory University and Children’s Healthcare of Atlanta

Historically, coagulopathy has been recognized as an accompaniment of severe trauma. Numerous studies have shown that coagulopathy is commonly observed in patients who have sustained trauma. For decades, it was believed that the coagulopathy was a late and iatrogenic effect of transfusion of crystalloid and red blood cells, resulting in a relative or absolute deficiency of clotting factors. More recently, it was shown that the coagulopathy occurs “early”. The purpose of this study is to define the profile of coagulopathy following TBI in children, to assess the degree of platelet dysfunction and its contribution to the trauma-induced coagulopathy, and to apply association rule mining technology to evaluate the utility of thrombo-elastography (TEG) in identifying the pathophysiological mechanism involved in TBI and to direct specific coagulopathy-correcting treatments. Patients admitted to the PICU for TBI are enrolled into the study. Study labs are added that include the addition of coagulation profiles to be collected serially in the first 48 hours following admission. In addition, all patients who have sustained a severe TBI will obtain admission platelet function assays (PFA) and TEG (Regular TEG) on arrival in the ED or ICU as well as subsequent daily PFA and Regular TEG. Testing will also occur at 24, 48, and 72 hours after admission.

Notable outcomes: NINDS R21 award

Chia-Yi (Alex) Kuan, MD, PhD, Emory University
David Archer, PhD, Emory University

Pediatric stroke is one of the most serious complications of sickle cell disease (SCD). Without treatment, 11% of SCD patients have clinically apparent stroke before the age of 20. In addition, silent cerebral infarct occurs in 27% of SCD children before their 6th, and 37% by their 14th birthdays. While chronic blood transfusion decreases the incidence of overt stroke, it triggers immune responses and iron overload, which may contribute to neurocognitive deficits of this population. Hence, the current state of preventive and acute treatment of SCD-related pediatric stroke needs further investigation and improvement. Proper use of transgenic sickle mouse models in experimental stroke may suggest new therapy, but surprisingly very little research has been conducted in this direction to this date. The GOAL of this pilot project is to establish a paradigm that is tailored for studying the cause and therapies of ischemic stroke in transgenic sickle mice. Once established, this experimental paradigm will open a multitude of research avenues.

Andrew P. Escayg, PhD, Emory University
Sandra L. Helmers, MD, MPH, Emory University and Children’s Healthcare of Atlanta

The idiopathic generalized (genetic) epilepsies (IGEs) encompass several syndromes characterized by agerelated (often childhood onset), recurrent, and unprovoked generalized seizures in the absence of detectable brain lesions or metabolic abnormalities. Although the etiology of IGE is genetically determined, genome-wide association studies for the most part have yet to identify any common IGE susceptibility loci. This is consistent with what is known as the common disease/multiple variant hypothesis, which predicts that a significant portion of IGE is due to relatively infrequent mutations in a large number of genes that influence neuronal excitability. Under such a model, efficient identification of IGE genes will require inexpensive methods for DNA sequence analysis, as well as access to DNA from large families segregating epilepsy-causing mutations. Fortunately, recent developments in high-throughput sequence analysis have led to cost-effective methods for direct sequencing of all the protein coding regions of an individual’s genome (called whole exome sequencing). Nevertheless, access to large epilepsy pedigrees remains limited, creating a bottleneck to efforts to identify IGE genes. To address this limitation, in 2004 our group began a collaboration with Dr. Sandra Helmers to establish a repository of DNA samples from families with extensive histories of epilepsy that are seen at the Emory Epilepsy Clinics. Over the years, we have received tremendous support from many of the nurses and clinicians, many of whom have referred patients to our study. This has resulted in a DNA repository that now contains samples from 85 families, with over 14 of these families having six or more affected individuals. With this unique and powerful resource in hand, the goal of our proposed pilot study is to identify novel epilepsy genes/mutations by performing whole exome sequencing (WES) on two affected members from each of ten families.

Han Phan, MD, Emory University
Tobey John MacDonald, MD, Emory University and Children’s Healthcare of Atlanta

Notable outcomes: Pediatric Brain Tumor Foundation award

Xiangyang Tang, PhD, Emory University

Trauma is the leading cause of death in children and traumatic brain injury (TBI) ranks No. 1 in the traumas causing death and claims ~7,400 lives in the nation annually. An appropriate identification and triage of pediatric patients with TBI due to head trauma, based on trauma mechanism and history, physical and neurological findings, and diagnostic imaging, is of paramount relevance in clinical practice. CT has been the reference standard for diagnosis of pediatric head trauma patients. In addition to the use of clinical guidelines for justification and pediatric specific CT protocols, a fundamental solution is to reduce the radiation dose needed to form a CT image with sufficient quality. We developed an optimization-based hybrid iterative dose reduction algorithm (HIDRA) for low dose CT. Based on encouraging preliminary data, we hypothesized that the HIDRA solution can reduce radiation dose in pediatric head CT by up to 65% while maintaining image quality. 

Elizabeth Mynatt, PhD, Georgia Tech
Cherise Frazier, MD, Emory University and Children's Healthcare of Atlanta
Cam Escoffery, PhD, MPH, Emory University

Co-sponsored by the Goizueta Foundation

Ann Chahroudi, MD, PhD, Emory University and Children's Healthcare of Atlanta
Jessica Raper, PhD, Emory University

Intense research has focused on the neurologic effects of prenatal Zika virus (ZIKV) infection; while, the consequences of postnatal infection early in life are understudied. The potential of ZIKV to cause ongoing damage after birth is evident in infants with fetal ZIKV exposure without microcephaly at birth, but develop postnatal microcephaly, neurologic dysfunction, and neurodevelopmental abnormalities later in life. This damage is likely related to the exponential maturation of the brain that occurs during the first 2 years of life, particularly in temporal, prefrontal and parietal regions important for emotional, social and executive functions, including learning, attention and memory. Our group has previously reported that postnatal ZIKV infection causes persistent abnormalities in brain structure, function, and behavior in infant rhesus macaques (RMs) infected postnatally. Here, we propose to examine a potential prophylactic treatment to prevent the negative impact of postnatal ZIKV infection on the developing brain. 

Notable outcomes: NINDS R01 award

Avanti Gokhale, PhD, Emory University

The overall focus of this proposal is to investigate the role of copper dyshomeostasis in childhood neurodegeneration using the Menkes disease as a model. Menkes disease is a genetic disorder caused by mutations in the copper transporter ATP7A resulting in severe neurodegeneration.  However, the molecular pathways that result in copper-mediated neuronal death remain largely unknown. Our recent work has uncovered a promising dataset of ATP7A interacting proteins that may provide a mechanistic link between copper imbalances and cell death. Of particular interest is the protein DJ-1 – a protein thought to be a copper chaperone and regulate mitochondrially localized cuproenzymes. We propose that ATP7A and DJ-1 functionally interact in a pathway that compromises mitochondrial function thus affecting energy consumption and respiration resulting in neuronal death. The experimental strategies described in this proposal will test this prediction and will reveal novel biomarkers, risk factors and therapeutic targets for those at risk for metal-mediated childhood neurodegeneration.

Notable outcomes: NIEHS R01 award

Asaad G. Beshish, MD, Emory University and Children's Healthcare of Atlanta

Coarctation of the aorta is one of the most commonly encountered congenital heart lesions in pediatric cardiac surgery, accounting for 5-8% of all pediatric patients with congenital heart disease (CHD) and with an overall incidence of 0.03% out of every 10,000 live births . While most patients who undergo coarctation repair are extubated without complication, there is a subset of patients who fail to extubate within the expected timeframe of immediately or within a few hours post-surgery. To this day, we do not know the etiology of why a subset of patients’ status post COA repair have delayed extubation for > 24 hours. We hypothesize that delayed extubation may be associated with dramatic changes in arterial blood pressure (ABP) after surgical intervention that affects cerebral autoregulation and result in decrease cerebral blood flow.

Laura S. Blackwell, PhD, ABPP,  Emory University and Children's Healthcare of Atlanta

Neonatal Encephalopathy (NE) is one of the top 20 causes of burden of disease in all age groups, in terms of disability life adjusted years, by the WHO, and is the 5th largest cause of death of children younger than 5 years. Surviving children are afflicted with varying degrees of motor and cognitive deficits. These deficits not only affect the child but also place a high emotional and financial toll on families, caregivers, communities and society at large. Despite improvements in therapeutics and advances in assessment methods, there still is a lack of objective, quick and inexpensive methods to identify brain injury and identify those who would benefit most from treatments. More recent studies on blood biomarkers have shown to aid in identifying severity if injury and predicting prognosis, although there is no consensus on the clinical utility in standard practice. Our project plans to collect pilot data on 10 neonates identified with moderate to severe NE at birth and follow them over the course of their admission in the NICU, collecting clinical evaluations along with novel plasma markers and MRI sequences. We aim to 1) Identify and address roadblocks to studying novel biomarkers in neonates with encephalopathy undergoing therapeutic hypothermia and 2) Evaluate OPN in the pilot cohort as a potential blood biomarker for identifying brain injury and detecting infants that need adjuvant neuroprotective therapies. 

Anna M. Kenney, PhD, Emory University
Tobey J. MacDonald, MD, Emory University and Children’s Healthcare of Atlanta
Robert Craig Castellino, MD, Emory University and Children’s Healthcare of Atlanta

Medulloblastomas arise in the developing cerebellum during childhood and are thought to result from aberrant regulation of neuro-developmental signaling pathways. These tumors are the most common malignant pediatric tumor of the central nervous system. Standard therapy for medulloblastomas occurring in patients greater than 3 years of age comprises surgical resection, radiation of the tumor bed and cranio-spinal irradiation as well as chemotherapy. This regimen is associated with a ~70% cure rate. However, survivors are beset with long-term neurological and cognitive side effects, and tumor recurrence is lethal and typically associated with metastasis. To ameliorate the need for toxic therapeutic approaches and to reduce the incidence of metastasis, development of targeted therapies is urgently needed.  As yet, single target therapies for medulloblastoma have failed in the clinic. We propose to combine targeting of three pathways together promoting medulloblastoma cell proliferation, apoptosis evasion, and metastasis; the proteins we will inhibit are STAT3, PPM1D, and IGFBP2.  We will first conduct in vitro cell culture proof-of-principle studies, followed by 3-dimensional organotypic slice culture analysis of radiation response in medulloblastomas derived from genetically engineered mouse models for Sonic hedgehog and Group 3 medulloblastoma, and finally, we will carry out pre-clinical studies in medulloblastoma-bearing mice to determine the effect of our combinatorial targeting strategy on animal survival in the presence and absence of radiation therapy.

Daniel L. Drane, PhD, ABPP(CN), Emory University

Current neuropsychological memory tests for children and adults lack complexity, hindering their ability to predict real-world performance, including functional outcome following neurosurgical intervention. Existing measures fail to integrate sensory input with personally relevant semantic content, never assess the temporal and spatial context of learning, and overlook long-term memory recall and consolidation during sleep. To address these limitations, we propose the Emory Pediatric Multimodal Learning Test (EPMLT) for memory assessment. The EPMLT utilizes professionally produced video clips to assess learning and recall of spatial features, actor characteristics, and observed objects. It incorporates eye tracking, EEG recordings, and the Unity Game engine for in-person or virtual testing. Our study aims to establish the EPMLT's psychometric properties, identify patterns of left- and right-hemisphere dysfunction, and compare it to traditional memory measures. We hypothesize that TLE patients will show greater deficits on the EPMLT, correlating more strongly with self-report and functional status. We anticipate baseline deficits in verbal memory for children with left TLE and limitations in face processing and visual memory for right TLE. We believe both groups will exhibit deficits in cross-modal learning and decay of acquired knowledge and expect that deficits will be more severe in post-surgical patients. This study will reshape pediatric memory assessment for all populations, which will contribute to improved models of memory processing, moving us closer to the complexity of processing that standard tests cannot explore, and will provide a much-needed tool for determining outcome risks in the surgical setting.