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Examples of UAB IDDRC Research by Project Leaders

David Bedwell
The Bedwell laboratory is examining the effect of the ability of aminoglycosides and other pharmacological agents have the ability to suppress stop mutations in the mucopolysaccharidosis MPS I-H related to deficiency of the lysosomal enzyme, iduronidase. Previous studies in this laboratory showed that the aminoglycoside gentamicin can suppress the IDUA Q70X and W402X premature stop mutations (carried by ~70% of MPS I-H patients) and restore enough a-L-iduronidase activity to normalize glycosaminoglycan levels in cultured primary fibroblasts derived from an MPS I-H patient [Keeling et al., Human Molecular Genetics 10: 291-299 (2001)]. To explore this novel therapeutic treatment further, we recently succeeded in constructing an /c/tya-W402X knock-in mouse in which the /DLW-W402X premature stop mutation found in MPS I-H patients was introduced into the corresponding position in the mouse Idua gene. This new mouse model will allow us to test the hypothesis that the suppression of premature stop mutations and/or nonsense-mediated mRNA decay (NMD) can restore enough a-L-iduronidase activity to correct the disease manifestations of MPS I-H in vivo.

Michael Brenner
The Brenner laboratory studies the molecular biology of astrocytes, the most common cell type in the central nervous system (CNS). Astrocytes are responsible for many of the homeostatic controls in the CNS, and are also involved in complex developmental and functional interactions with neurons and oligodendrocytes. His work focuses on the transcriptional regulation of a gene encoding an intermediate filament protein specific to astrocytes, glial fibrillary acidic protein (GFAP), and on the biological role of this protein. The GFAP gene is of interest because it is turned on as astrocytes mature, and its activity increases dramatically following almost any CNS injury. Thus, study of GFAP transcription will yield insights into mechanisms governing development, reaction to injury, and cell specificity. An important role for the GFAP protein is indicated by the fact that astrocytes have elaborated their own specific intermediate filament protein and by its greatly increased synthesis following injury. In transcriptional studies he has identified a GFAP promoter segment that permits transgenes to be expressed specifically in astrocytes, making it possible to test hypotheses about the function of almost any gene product in the CNS of a living animal. The GFAP promoter is also used for creation of disease models and for genetically modifying astrocytes for gene therapy. In studies of GFAP function, we has found that absence of the protein renders mice hypersensitive to traumatic spinal cord injury, revealing a novel role for GFAP in structural support. We have also discovered that mutations within the coding sequence of the GFAP gene are responsible for many cases of Alexander disease, a rare disorder of humans that causes profound mental retardation. These studies have led to a new diagnostic screen for parents to evaluate risk of Alexander’s disease in children.

Bill Britt
Dr. Britt’s lab is primarily interested in identifying the molecular components, the routes of infection and the effects of prenatal exposure to human cytomegalovirus (hCMV) infection on fetal brain development. He uses a molecular virology approach to characterize the proteins of the infectious agent and has developed an animal model to study how hCMV exposure perinatally, interacts with cell migration in the developing cerebellum. He studies the effects of CMV exposure in humans and in the animal model in order to best identify the process at the basic molecular level that give rise to the actual phenotype of the disorders (particularly effects on hearing loss in children) and what underlying brain abnormalities may contribute to this and other neurological effects of exposure to the virus. In addition, the Britt laboratory will examine an intriguing finding that suggests that cytomegalovirus promotes the development and progression of gliomas. Together, these diverse projects with the common focus on CMV should offer important therapeutic avenues for the prevention or amelioration of developmental and neoplastic disorders of the CNS.

Wally Carlo
Dr. Carlo studies the underlying mechanisms and potential therapeutic interventions for a wide range of neurodevelopmental disorders to which babies of low birth weight are particularly susceptible including neonatal pulmonary disorders, neonatal apnea, neonatal ventilation, and respiratory distress syndrome. Birth asphyxia is a leading cause of neonatal mortality and morbidity in developing countries. Survivors of birth asphyxia have high rates of mental retardation, cerebral palsy, and other neurodevelopmental disorders. Controlled trials and meta-analyses conclude that early intervention programs prevent or minimize cognitive impairment in many high-risk infants. These programs are legislatively mandated in the United States and are the standard of care in developed nations. However, early intervention programs are rarely available in developing countries and thus, to most at-risk infants worldwide. Preliminary evidence from a small randomized controlled trial conducted in a developing country suggests that a program of home-based early intervention improves neurodevelopmental outcome (Mental Developmental Index) in survivors of birth asphyxia but conclusive evidence is not available. Pilot data obtained as part of a planning grant funded by an R21 documented the high prevalence of sequelae for birth asphyxia and feasibility of an early intervention program. The current application aims to identify infants at risk for neurodevelopmental disorders and to evaluate an innovative early intervention program in developing countries utilizing established multidisciplinary collaborations between researchers in the US, Zambia, India, and Pakistan who currently work as part of the NICHD Global Network for Women's and Children's Research on an early phase of the FIRST BREATH multicenter cluster randomized trial on resuscitation. A randomized controlled trial of early intervention will be performed in infants with birth asphyxia identified by abnormal neurological exam during the first week after birth and in normal a comparison group. A home-based, parent-provided, early intervention will be tested in two delivery modes: resource-intensive and resource-limited. If proven effective in developing countries, a home-based early intervention program has the potential of improving cognitive capacity in many at-risk infants worldwide at a cost lower than more expensive special education services. The long term goal of this proposal is to broaden research collaborations and to build sustainable capacity for research to prevent or reduce neurodevelopmental sequelae resulting from birth asphyxia and other important causes of neurodevelopmental impairment in children.

Candace Floyd
Recently, 17a-estradiol was found to be beneficial in SCI which suggests that estrogen receptors (ERs) could be therapeutic targets. Estrogen binds with equal affinity to two subtypes of the ER, the classical ERa and the more recently discovered ERa. A clue that selective ERp activation may confer protection is SCI comes from studies of plant-derived estrogens, or phytoestrogens. Genistein, a phytoestrogen from soy and a preferential ERp agonist, dose-dependently confers protection in models of neuronal injury and cardiac ischemia. We hypothesize that selective activation of the ERa by genistein will produce significant protection in SCI. We will test this hypothesis by administering either a low, medium or high dose of genistein 30 minutes after a moderate thoracic spinal cord injury in rats. An additional group will receive co-administration of genistein and the ER antagonist ICI 182,780. We will also administer genistein with and without the ER antagonist ICI 182,780 and evaluate sub-acute markers of secondary injury including locomotor impairment, white matter sparing, lesion volume, and lower urinary tract function. These experiments explore the clinically relevant possibility that preferentially targeting the non-feminizing ERa is neuroprotective by evaluating the neuroprotective potential of a natural, plant- derived estrogen, genistein.

Russell Kirby
The Alabama Autism Surveillance Project (AASP) will conduct surveillance of autistic spectrum disorder, mental retardation, and cerebral palsy in a 32 county area of north Alabama including the metropolitan areas of Birmingham, Tuscaloosa, Huntsville, and Decatur. In calendar year 2000, there were 36,209 live births to residents of the study area. The project will be conducted by the University of Alabama at Birmingham as the bona fide agent of the Alabama Department of Public Health, and Dianne Sims, RN, BSN, Director, Child Health Branch, will be the liaison from the state health agency. The AASP will implement a surveillance strategy compatible with case-finding methods in use in other ADDM projects designed to identify, abstract, review and validate cases of ASD, IDD, and CP among children age 8 living in the 32 county study area during calendar year 2002. The primary objective is to identify all children in the study area with these developmental disabilities, and create an unduplicated epidemiologic dataset with demographic and diagnostic information on each of these cases. The project includes process and outcome evaluations to measure the completeness and efficiency of surveillance procedures. Upon completion of the study, we will have a clear picture of the descriptive epidemiology of ASD and related developmental disabilities, characterized by gender, race/ethnicity, urban/rural location, and socio-demographic correlates from vital statistics data, both in Alabama and in collaboration with ADDM/CADDRE sites, across the nation. This will provide a foundation for etiologic research, strategies for early diagnosis and treatment, the development of more effective interventions and services to children and families with ASD, and a better understanding of ASD in the community.

Jayne Ness
Dr. Ness investigates perinatal hypoxic ischemic injury is a common cause of neurologic disability mediated at least in part by Bcl-2 family dependent neuronal apoptosis. The Bcl-2 family consists of both pro- (Bax, Bad, Bid, Bim) and anti-apoptotic (Bcl-2, BcI-XL) proteins that regulate mitochondrial function, cytochrome c release and caspase activation. Bcl-2 family function is in turn, regulated by neurotrophic factor-induced phosphorylation and modulation of this pathway is an attractive therapeutic target for limiting the neuropathological consequences of perinatal brain injury. Previous studies have implicated Bax as an important mediator of neuronal cell death in several models of brain injury, including neonatal HI. Dr. Ness is testing the hypothesis that specific BH3 domain-only members of the Bcl-2 pro-apoptotic subfamily will regulate Bax-dependent neuronal cell death in the neonatal brain and that the known (NGF, BDNF) or potential (neuregulin) neuroprotective effects of neurotrophic factors in neonatal HI brain injury are mediated through the regulated phosphorylation of BH3-only Bcl-2 family members. She utilizes wild-type and transgenic mice deficient in specific pro-apoptotic BH3-only proteins (Bad, Bim, Bid) and other apoptosis-associated proteins in two models of neuronal HI.