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Examples of UAB IDDRC Research by Project Leaders

Thomas Novack
The Novack laboratory examines therapeutic approaches to diffuse axonal injury (DAI). DAI causes a reduction in the turnover of dopamine in the brain. Basic science research has suggested that increasing dopamine turnover at the synaptic level may have a beneficial effect on recovery from brain injury. One medication, Amantadine, has been the subject of considerable interest and clinical use. It stimulates the release of dopamine from the presynaptic neuron, inhibits the re-uptake of dopamine, may directly interact with post-synaptic dopamine receptors and is a weak N-methyl-D-aspartate (NMDA) antagonist. This concept study, or any other(s) selected, will contribute to the multicenter TBI Clinical Trials Network. The study design is a single case double blind, randomized controlled trial. Utilizing well established outcome measures, including behavioral and cognitive, the investigators will attempt to establish the efficacy and side effects of Amantadine in the acute stages of recovery from TBI. This research has the significant possibility of reducing the disability and economic burden of these patients.

Michael Passineau
The Passineau laboratory is taking advantage of the intrinsic endocrine pathway in salivary gland capable of robust synthesis and secretion of non-regulated (i.e. constitutive) gene products into the vascular space as a result of retroductal administration of a gene therapy vector to evaluate enzyme replacement therapy in Fabry disease, a member of lysosomal storage diseases. Studies are designed to develop salivary gland-based gene therapy strategy for Fabry disease in the mouse knockout model, B6;129-Gla(tm1/Kul/J), an alpha-Galactosidase A (-/O) model by testing the hypothesis that an AAV vector containing the sequence for human alpha-Gal A delivered to the salivary glands in alpha-Gal A deficient "Fabry" mice will result in systemic replacement of the enzyme and reversal of the specific systemic biochemical defect underlying Fabry disease. These studies will produce important insights into the technical parameters of this system, including: longevity of transgene expression, host immune response, and mitigation of Fabry-associated pathology, and form the basis whereby other systemic disorders could be addressed using salivary glands as the biosynthetic site for systemic therapeutics.

Alan Percy
During the past fifteen years, Dr. Percy has focused his research activities primarily on Rett syndrome (RS). Initially, these studies related to understanding the integral clinical components of RS. These included analysis on clinical neurophysiologic aspects related to epilepsy and sleep characteristics, understanding the pattern of and basis for pervasive growth failure, developing population-based prevalence data, and exploring the molecular bases for this unique disorder. With the identification of mutations in MECP2 in the overwhelming majority of individuals with RS, efforts then shifted to understanding phenotype-genotype correlations and exploring the variant clinical expressions of individuals with such mutations but lacking some or all of the characteristic features of RS. These studies are accomplished in close collaboration with Dr. Daniel Glaze and Dr. Huda Zoghbi at the Baylor College of Medicine and with Dr. Carolyn Schanen at the Nemours Institute in Delaware. Very recently, Dr. Percy co-organized and coordinated a placebo-controlled trial of folate and betaine in RS and more recently a systematic study of cerebrospinal fluid folate levels in RS. Both projects represented components of the PPG (Huda Zoghbi, PI) and the recently funded multi-site Rare Disease CRC project (Arthur Beaudet, PI). During the past year, Dr. Percy in collaboration with Dr. Fred Biasini has led a multi-institutional study of the effects of PCBs on neurocognition and neurobehavior in Anniston, AL. This project, funded by the Agency for Toxic Substances and Disease Registry, is now in its analytical phase with no additional funding.

Thomas Ryan
The research in our laboratory is focused upon understanding basic mechanisms of gene regulation in order to develop and subsequently cure animal models of human disease. Knowledge gained from our studies of the high-level, tissue-specific, and temporally regulated expression of human globin genes in transgenic mice have enabled the generation of mouse models of sickle cell disease and beta thalassemia that faithfully mimic and reproduce most if not all of the pathology of the disorders. Embryonic stem (ES) cells have multiple qualities that make them invaluable for the production of genetically modified mice. These same characteristics also make them an ideal tool for future cell based therapies. We are developing ES cell based therapies to model the correction and cure of inherited genetic disease utilizing our mouse models of beta thalassemia and sickle cell disease. ES cells derived from somatic cells of diseased mice are corrected by homologous recombination and differentiated in vitro to hematopoietic stem cells for transplantation back into the diseased animals. The long-term goals of this project are the development of therapeutic methods that are efficient, reproducible, safe, and translatable to human therapy. Consequently, the laboratory is also modeling some of these methods in one of the federally approved human ES cell lines (WA01). We have recently initiated a mutagenesis screen in mice to identify genetic modifiers of sickle cell disease. This phenotype driven approach utilizes ES cells derived from our knock-out transgenic and knock-in animal models of sickle cell disease. Sickle ES cells are chemically mutated with N-ethyl-N-nitrosourea (ENU), subcloned into mutant cell lines, and cryo-preserved. After thawing, sickle mice are produced from the mutant ES cell lines and examined for variation in their disease severity. Additionally, mutant sickle ES cell lines harboring mutant genes of interest are identified by screening DNA purified from our mutant ES cell library. This prescreening for mutations allows the production of sickle mice for study that have known mutations in genes of interest.

Harald Sontheimer
Glial cells constitute over 50% of brain cells, yet their involvement in normal brain function is not fully understood. It is clear that unlike neurons, glial cells can proliferate in the adult brain and are of crucial importance in mediating the brains response to brain injury. Proliferating glial cells in which growth control has been lost give rise to primary brain tumors, astrocytomas or glioblastomas, the most deadly form of cancer. It is thus increasingly clear that a number of neurological conditions are associated with or caused by compromised glial function. The goal of the Sontheimer laboratory is to understand how glial cells contribute to neuronal function in the healthy and diseased brain. They are particularly interested in the role of glial cells as K+ and pH buffers and as depository of neuronally released glutamate. Studying signals involved in neuron-glial interactions during development, regeneration and myelination are a priority. He uses patch-clamp electrophysiology, quantitative ratiometric fluorescence cell imaging and radioisotope flux techniques to study movements of ions across glial cell membranes. He compares properties of normal glial cells to those of glial tumors and seizure associated "scarring" glial cells to understand potential involvement of ion channels and carriers in cell proliferation and disease. Since neurons and glial cells have the potential to influence each other through the release of neuroligands and growth factors, the Sontheimer lab is studying possible neuron-glial interactions in vitro using selective agonists and antagonists to second messenger pathways along with co-culture systems of well defined neurons and glial cells.

David Standaert
The Standaert laboratory is examining two basal ganglia related proteins, torsinA and alpha-synuclein in order to elucidate the neural mechanisms of dystonia and transcriptional dysregulation, respectively. Both problems are related to abnormalities in dopamine metabolism, cholinergic function, and striatal dopamine/glutamate interactions. Proposed studies will examine the localization and function of torsinA in genetically engineered rodent models, an essential step in the construction of mechanistic models of the dystonia in general and DYT1 dystonia in particular. The mechanism by which alpha-synuclein exerts a toxic effect is unknown. One potential mechanism is transcriptional dysregulation, that is, interference with the expression of cellular genes essential for normal function. To determine whether alpha-synuclein aggregates in human disease or animal models lead to transcriptional dysregulation, an array-based approach will be utilized. A transgenic model of synucleinopathy will be employed to determine whether restoring the expression of dysregulated genes can ameliorate the disease process. Both studies seek a better understanding of the basic mechanisms and new approaches to treatment.

Edward Taub
Edward Taub is a behavioral neuroscientist who developed a new family of techniques, termed Constraint-Induced Movement therapy or CI therapy, which has been shown to be effective in improving the rehabilitation of movement after brain injury. This work is derived from basic research he carried out with deafferented monkeys whose upper extremities had been surgically deprived of sensation. CI Therapy consists of a family of therapies; their common element is that they teach the brain to functionally "rewire" itself (most likely through mechanisms that involve changes in synaptic function after training periods) following a major injury such as stroke traumatic brain injury or in certain forms of developmental disorders such as the hemiplegic form of cerebral palsy. This is based upon research carried out by Dr. Taub, and collaborators showing that patients can "learn" to improve the motor ability of the more-affected parts of their bodies and thus cease to rely exclusively or primarily on the less-affected parts. These therapies have significantly improved quality of movement and substantially increased the amount of use of a more-affected extremity in the activities of daily living for a large number of patients.

Tim Townes
The major research interest of Dr. Townes laboratory is the regulation of gene expression during development. A classic model of developmental control in eukaryotes is the temporal-specific switching of hemoglobins. In order to investigate the molecular mechanisms involved in globin gene regulation, he has introduced human fetal (g) and adult (b) globin genes into fertilized mouse eggs. Both human g- and b-globin genes are correctly regulated in the transgenic mice that develop. The human g-globin gene is expressed early and turned off late, and the b-globin gene is expressed late but not early. Precise definition of the sequences responsible for this temporal-specific control and identification and isolation of the proteins that interact with them are major goals. Sequences located far upstream of the human b-globin locus have a dramatic effect on the globin gene expression. These sequences are characterized by extreme sensitivity to DNase I digestion in isolated nuclei. The hypersensitive (HS) sites are erythroid-specific but developmentally stable. They are present in embryonic, fetal and adult erythroid cells. Transgenic mouse experiments suggest that these sequences have two distinct and important functions. First, they organize the entire b-globin locus into an "open" or DNase I sensitive domain. Second, they serve as a powerful enhancer of e-, g- and b-globin gene transcription. Another goal of Dr. Townes’ work is to produce a mouse model of human sickle cell disease. As a first step toward developing this model, we have produced mice that synthesize high levels of functional human hemoglobin. The human hemoglobin purified from erythroid cells of these animals has the same oxygen binding characteristics as hemoglobin purified from human red blood cells. Recently, we produced transgenic mice that synthesize high levels of human sickle hemoglobin. He plans to introduce new genes into bone marrow from these sickle cell mice in an attempt to cure the disease. So far, he has constructed retroviral and AAV vectors containing human g- or b-globin genes inserted downstream of the HS sequence. He is testing these viruses for the ability to transfer functional globin genes into bone marrow stem cells.