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Examples of UAB IDDRC Research by Project Leaders

Donald Twieg
The Twieg laboratory proposes a new approach to data acquisition and analysis in fMRI. Contemporary magnetic resonance imaging (MRI) methodology involves an implicit assumption, which is computationally convenient but physically inaccurate. This R21/R33 project seeks to develop a novel fMRI methodology which abandons this assumption, thereby avoiding defects which commonly afflict rapid single-shot MRI images. Because it interprets fMRI raw data more accurately, the new methodology promises also to permit fundamentally more efficient, accurate and robust measurements to be made in several general types of fMRI applications, such as diffusion imaging, measurement of tissue relaxation parameters, flow and motion imaging, and blood perfusion imaging. This approach measures tissue parameters more directly than do established approaches, which infer parameters from multiple separately acquired images. In an initial investigation and development of this methodology (termed PARSE), this project will implement a single-shot PARSE method, SS-PARSE, which is especially well-suited to functional MRI (fMRI) of the brain, with several theoretical advantages over existing methods used in fMRI. The immediate goal of this study will be to verify these expected performance advantages of the SS-PARSE technique in well-controlled imaging studies using phantom objects in a 4.7T vertical-bore primate MRI imaging system. A shortcoming of the methodology is that it requires much longer computation times than conventional fMRI approaches. This project seeks to develop much faster computational algorithms and determine the prospects for reducing computational time to roughly that of typical conventional fMRI studies. The project promises to introduce a new methodology yielding substantial performance benefits over a broad range of fMRI applications.

Shu-Zhen Wang
The Wang laboratory studies the molecular regulation of photoreceptor production in the vertebrate retina. This knowledge is imperative to the development of effective stem cell-based photoreceptor replacement therapies. Much needs to be learned about the identities of the genes involved and how they contribute to the selection of the photoreceptor fate from among the other options. Proposed studies will test the hypothesis that photoreceptor production employs ngn1 at a key step between ngn2 and neuroD. These studies utilize a battery of techniques from molecular biology, cell biology, developmental biology, and genetics. This project promises to shed light on the transcriptional regulation governing photoreceptor production. The identification of key genetic players in photoreceptor production could lead to efficient in vitro or in vivo photoreceptor generation for studies with therapeutic goals in this era of heightened interest in stem cell research for replacement therapies.

Richard Whitley
Dr. Whitley studies genetically engineered HSV-1 (HSV) as a novel, yet practical approach to the treatment of human brain tumors, generating molecular biologic data on genetically engineered HSV to translate observations to phase I clinical trials of human glioblastoma multiforme. Whitley and his colleagues are constructing novel therapeutic HSV that specifically targets cell surface receptors expressed specifically and at high abundance on glioma cells in situ. Whitley is generating viruses with enhanced oncolytic potential for human gliomas and determining whether viruses selected with novel properties demonstrate enhanced neurovirulent properties.

Phil Wood
Dr. Wood’s research interests are focused on the genetic regulation of fatty acid metabolism and the role of dysfunctional fatty acid metabolism in disease. He currently has three main areas of interest in the laboratory: 1. He is interested in the inborn errors of mitochondrial fatty acid beta-oxidation. These are relatively rare disorders mostly of young children. These children have severe intolerance to fasting. Their disease episodes occur as a response to fasting, or other severe metabolic stress, and result in acute hypoglycemia, fatty liver, metabolic acidosis, cardiac disorders and sometimes sudden death. In order to study these diseases, we have developed five different mouse models of mitochondrial enzyme deficiencies including carnitine palmitoyltransferase-1a (CPT-1a – liver isoform), very long-chain dehydrogenase (VLCAD), long-chain acyl-CoA dehydrogenase (LCAD), medium-chain acyl-CoA dehydrogenase and short-chain acyl-CoA dehydrogenase (SCAD). All except SCAD deficiency were produced by gene targeting. 2. using the fatty acid metabolism pathway as a “candidate pathway” for understanding the genetics/genomics of insulin resistance and type 2 diabetes mellitus. (To that end he is looking at interactions between genomes and nutrition that promote for the problems of excess fatty acids in the body combined with deficient fatty acid oxidation). This problem of excess fatty acids is pivotal in the development of insulin resistance and diabetes. These studies involve investigating the interactions of quantitative trait loci that promote for insulin resistance/diabetes in combination with inherited defects of fatty acid oxidation, and how diets with high amounts of simple carbohydrates further aggravate the development of these diseases. and 3. drugs used to treat AIDS patients that appear to induce severe lipid disorders that include lipodystrophy, dyslipidemia, and mitochondrial toxicity. Current treatments include use of HIV protease inhibitors (PI) combined with nucleoside reverse transcriptase inhibitors (NRTI) in a combination known as highly active antiretroviral therapy (HAART). He is investigating the roles these drugs may have in disrupting the regulation of fatty acid synthesis and fatty acid oxidation, and if inherited defects in mitochondrial fatty acid oxidation constitute a genetic predisposition for development of mitochondrial toxicity

James Cox
Food cues, especially from foods high in fat and calories, may trigger overeating in obese individuals. The neural basis of this effect is thought to be exaggerated activity within a distributed circuit referred to as the reward system, which includes such brain regions as the amygdala and orbitofrontal cortex. The proposed studies will use functional magnetic resonance imaging (fMRI) to compare reward-system activation elicited by pictures of high and low calorie foods in obese participants in a 12-week weight loss program vs. normal-weight controls. In the first study, fMRI scans will be performed prior to the program to test the predictions (1) that food images, especially of the high calorie foods, elicit greater reward-system activation in the obese men and women than in controls and (2) that degree of activation will predict subsequent weight loss, such that obese individuals with the greatest activation will lose the least weight. For the second study, scans will be performed after completion of the program. This study will test the prediction that those obese individuals whose elicited activity has been most normalized over the course of the treatment, will be those who show the greatest weight loss, both by the end of the program and at one-year follow-up. Both studies will also investigate the relationship of psychological variables -- appetite stimulated by food images, ratings of the emotional valence of the food images, reward sensitivity, and dietary restraint -- to brain activation patterns and to weight loss. We wish to determine whether long-term weight-loss is related to the amount of activation elicited by these images prior to the program and to the degree to which activation is normalized in a scan after completion of the program.

Susan Davies
The primary objective of the Davies project is to conduct a randomized clinical trial to evaluate the efficacy of a 6-week, theory-based, behavioral intervention to enhance positive parenting skills among HIV+ mothers. We will recruit 240 participants from among women receiving services at the UAB 1917 Clinic, the Children’s Hospital Family Clinic, AIDS Alabama, or AIDS in Minorities. Participants will be randomized either to an attention control condition or to a theory-based skills training condition that systematically addresses specific psychosocial issues associated with parenting as an HIV+ mother. The primary outcome measure to evaluate parenting outcomes will be use of positive parenting behaviors, measured by the Parent Practices Scale. The secondary outcome measures will be physical and mental maternal health status, measured by the MOS-HIV, and children’s behavior, measured by the CBCL. Additional measures collected will include parenting self-efficacy, overall parenting stress, children’s reports of parental behaviors, and behavioral observations of parent-child interactions. Depressive symptoms, hopelessness, household composition, child temperament and serostatus, and parents’ social support will also be assessed to examine theoretical assumptions regarding the relationships between these constructs and parenting. Outcome measures will be collected at baseline and at weeks 6, 18, and 30 to provide effective interventions for the behavioral and social issues faced by HIV-affected families.

Kent Keyser
The Keyser laboratory is examining the hypotheses that 1) nAChR subtypes are differentially expressed in specific amacrine and ganglion cells types; 2) specific nAChR subtypes serve different functional roles in retina; and 3) these differences are reflected in their differential subcellular distribution. Functional nAChRs expressed on ganglion cells will be studied with electrophysiological methods. The effects of subtype-specific agonists and antagonists on light responses of physiologically characterized ganglion cells will be studied, and effects of subtype-specific reagents on synaptically isolated cells' responses to cholinergic agonists will be evaluated. Antisera against synthetic peptides corresponding to unique sequences of mammalian alpha and beta subunits will be generated. These will be used to determine the subunit composition and abundance of nAChR subtypes. To identify nAChR-expressing cells in mammalian retina: Antibodies and antisera against alpha and beta subunits will be used to determine patterns of expression in rabbit retina, nAChR-expressing cells will be identified based upon their content of neurotransmitters, enzymes, or other molecular markers as revealed by double label studies. The subcellular localization of nAChRs will be studied by electron microscopy to determine if the nAChRs are associated with synapses only in the strata that contain the cholinergic cell dendrites.

Bruce Korf
Studies of the natural history, diagnosis, and management of neurofibromatosis type 1 (NF1) have been conducted over a period of nearly 20 years. These studies include the diagnostic outcome of children presenting with multiple cafe-au-lait spots, learning disabilities in NF-1, and abdominal migraine in children with NF-1. In the laboratory, a fluorescence in situ hybridization assay has been developed to detect the occurrence of large deletions involving the entire NF1 gene. More than 15 patients with such large deletions have been identified and studied phenotypically. They have a distinct phenotype of dysmorphic features, early onset and large number of neurofibromas, and severe developmental impairment. This is the only genotype-phenotype correlation so far established in NF1. A major clinical research project is ongoing involving study of the natural history of plexiform neurofibromas in NF1. This involves coordination of more than 15 clinical centers worldwide that will provide IDDI data to be used in quantitative analysis of the patterns of growth of plexiform neurofibromas. The study will provide normative data on tumor growth, test the efficacy of volumetric IDDI, and establish a network of centers to conduct clinical trials of potential therapeutic agents. Ongoing genotype-phenotype studies of NF1 include quantitative analysis of the NF1 phenotype and correlation with NF1 gene mutations as well as SNP’s in candidate modifying genes.

Ludwine Messiaen
Dr. Messiaen's research has focused on issues of molecular genetic testing in common and rare hereditary disorders (either in a presymptomatic, diagnostic or prenatal setting). Special areas of interest include sensitivity and specificity of the testing and strategies to develop comprehensive testing especially in large and complex genes, methods for automation of testing, costs and ethics. Dr. Messiaen's lab developed a cascade of complementary mutation detection techniques to define the unbiased mutational spectrum in the large NF1 tumor suppressor gene: "Using this strategy we identify the mutation in >95% of NF1 patients fulfilling the NIH diagnostic criteria. Similar approaches were applied to obtain equally high detection efficiency in other large genes, such as the NF2 gene. In order to search for possible genotype-phenotype correlations we link the genotypic data to a checklist documenting the phenotype. Simple genomic sequencing of a patient’s gene involved in a given hereditary disorder, frequently leads to the identification of so called ”unclassified variants”, posing diagnostic dilemmas. Hence, application and development of methods to distinguish benign variants from true pathogenic lesions is highly desired. Hereto, the study of the effect of the alteration at the mRNA level can be clarifying. We study the effect of all NF1 mutations at the mRNA level, which lead to the identification of several splicing mutations in the NF1 gene that would erroneously be considered as nonsense, missense or even silent if only genomic DNA would be studied. These studies lead to novel insights into the complexity of NF1 splicing. Furthermore, we have characterized several NF1 splice variants, not previously identified, and their tissue-specific expression is further investigated. Now that we defined the NF1 mutational spectrum in classic NF1 patients fulfilling NIH criteria, we started to study the molecular basis of some clinical subtypes, such as segmental NF, familial café-au-lait spots, spinal NF and NF1 with generalized peripheral nerve sheath tumors, as an approach to find genotype-phenotype correlations and to search for genes modifying the phenotype. In patients presenting with segmental NF, affecting only a specific region of the body, we study specific neural-crest derived cells from the biopsied lesions in order to define the molecular basis."

Burt Nabors
Research efforts are focused into three major areas. The first is a basic effort to understand the role post-transcriptional processes play in cancer initiation and progression. I am investigating the role of post-transcriptional regulation of gene expression in primary brain tumors, particularly tumors of astrocytic lineage. I am focused on growth factors, cytokines, and regulatory genes involved in proliferation, survival, angiogenesis and invasion. RNA stabilization is an emerging area of importance in the control of mRNA levels. I am interested in factors important in stabilization (RNA-binding proteins) and the signaling pathways which control this level of gene regulation. The second area of research interest takes advantage of my engineering background and appointment in the School of Engineering. We are interested in the acquistion and post-processing of magnetic resonnance imaging data in patients with primary brain tumors. We are particularly interested in the utility of perfusion and diffusion tensor imaging as non-invasive modalities to evaluate tumor angiogenesis, proliferation, and invasion. This effort compliments our early phase evaluation of novel glioma therapies. The third area of interest is the logical extension of the first two for a physician-scientist and involves the early phase clinical evaluation of novel cancer therapies. This includes the design and implementation of trials for newly diagnosed and recurrent malignant glioma that utilize biologically targeted strategies and includes non-invasive endpoints in the evaluation of a biological effect.