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Examples of UAB IDDRC Research by Project Leaders

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.

J. David Sweatt
This project focuses on the role of signal transduction mechanisms in long-term potentiation (LTP) and memory formation, critical factors in hippocampal synaptic plasticity and learning. These studies were initiated about 10 years ago in hippocampal slices and have transitioned to studies in the behaving animal and discovered that extracellular signal-regulated kinase (ERK) is activated in the hippocampus with contextual associative conditioning and that ERK activation is necessary for fear conditioning and for spatial learning in the Morris water maze. Studies from a wide variety of laboratories have now shown that MAPK signaling is involved in many forms of synaptic plasticity and learning, in essentially every species that has so far been examined. Given the clear importance of understanding the roles and regulation of ERK in synaptic plasticity and learning, the Sweatt laboratory will pursue studies related to the hypotheses of a role for the scaffolding protein Kinase Suppressor of Ras (KSR) in hippocampal ERK activation, LTP, and hippocampus-dependent memory, that Histone Acetyl Transferases (HATs) are a target of ERK regulation in the hippocampus, and that the dual-specificity MAPK phosphatase MKP-3 is a negative feedback regulator of ERK. These studies will give us insights into key functional loci in the hippocampal ERK MAP Kinase cascade, a new signal transduction pathway involved in transcriptional regulation, synaptic plasticity, and memory formation.

Qin Wang
The Wang laboratory studies the mechanisms by which alpha-2AR functions are regulated at the molecular and cellular levels, so as to provide new insights for therapeutic strategies. The properties of different agonists in stimulating various alpha2-AR-mediated responses and in inducing alpha2-AR internalization and subsequent sorting in native cells are the bases for alpha2-AR physiological functions. The proposed studies will utilize a mouse line in which N-terminal epitope-tagged HA-alpha2A-AR expression is driven by the endogenous mouse alpha2A-AR locus (HA-alpha2A-AR knock-in) to evaluate regulation of alpha2A-AR trafficking and signaling by two agonists, clonidine and guanfacine, in comparison with the endogenous ligand, norepinephrine, in native neocortical neurons. Our hypothesis is that the difference between these two agonists in eliciting in vivo responses is due to their diverse capabilities in inducing alpha2A-AR trafficking and signaling responses in native neurons. Revealing the molecular and cellular basis of alpha2-AR regulation by different agonists is crucial for guiding the development of alpha2-AR agonists in ADHD treatment as well as in other clinical settings where use of alpha2AR-agonists may be warranted.

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.

Scott Wilson
The identification of genes involved in neurodegeneration is a powerful means to understand the mechanisms of neuronal cell loss. Dr. Wilson identifies these genes through a variety of approaches in mice that include transgenics, gene-knockouts and positional cloning. He has recently cloned the mouse neurological mutation ataxia. The ataxia mouse displays a severe tremor and hind limb paralysis by 5 weeks of age. He showed that ataxia gene encodes Usp14, a member of the ubiquitin/proteosome pathway. During our analysis of the ataxia mouse, we found that loss of Usp14 results in synaptic transmission defects in both the central and peripheral nervous system. Since the members of this pathway act on a variety of substrates, we believe that the identification of the substrate(s) for Usp14 will provide important insights into the pathogenesis of the ataxia tremor and paralysis. In addition to Usp14, we are also investigating the function of several other members of the ubiquitin/proteosome pathway that are involved in neuronal function. The mouse waltzer mutation is another mutation that he recently cloned. The waltzer gene encodes Cdh23, the newest member of the cadherin superfamily. Loss of this gene product in humans results in both auditory and vestibular dysfunction. We are currently producing antibodies and generating other alleles of Cdh23 to understand how this gene product functions in the perception of sound and maintenance of balance. In addition to these projects, he is also in the process of identifying other spontaneous neurological mutations in mice, taking a candidate gene approach to identify the mutated genes in other neurological mice.

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

Etty (Tika) Benveniste
The Benveniste laboratory is studying the inflammatory events in the central nervous system (CNS) related to Multiple Sclerosis (MS), Alzheimer disease (AD), and Spinal Cord Injury (SCI). Activated macrophages/microglia are central to this response due to production of a wide array of cytokines, chemokines, matrix metalloproteinases and neurotoxins, and ultimately to glial/neuronal injury and death. We hypothesize that aberrant CD40 expression by macrophages/microglia, induced by cytokines such as IFN-gamma and TNF-alpha, contributes to inflammatory responses in the CNS. We also propose that strategies to suppress CD40 expression will attenuate inflammation and neuronal damage within the CNS, which will ultimately be of benefit in MS, AD and SCI. The mediators that regulate expression of CD40 in macrophages/microglia (both induction and inhibition) function at the level of gene transcription, thus it is imperative that we gain a better understanding of the molecular mechanisms involved in these responses. We will elucidate the contribution of the TNF-alpha signaling pathway and subsequent NF-kappaB activation to IFN-gamma induced CD40 gene expression in macrophages/microglia and determine the interactions between STAT-1alpha and NF-kappaB transcription factors and the CD40 promoter, and between transcription factors and various co-transactivators including CBP, p300 and CARM1, to understand CD40 gene expression. We will also determine the molecular mechanism(s) underlying suppression of CD40 expression in these cells. Our proposed studies will provide a comprehensive assessment of CD40 production and function in macrophages/microglia, thereby setting the foundation for future therapeutic manipulation of this critical immunoregulatory protein.

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.

Shannon Ross
The Ross laboratory is examining congenital Cytomegalovirus (CMV) infection, a leading cause of sensorineural hearing loss (SNHL) in children. The variable penetrance of SNHL has been argued to result from differences in host responses to this virus, yet CMV is a complex virus with well documented genetic and phenotypic variability among clinical CMV strains. We hypothesize that specific virus-encoded functions are responsible for an adverse outcome of intrauterine CMV infection and the variability in disease could be reflected in the diversity of viral genotypes and therefore, the phenotypic variability of CMV isolates. We propose several interrelated experimental approaches to investigate the role of genetically unique strains of CMV in the development of SNHL. Initially, the biological behavior of viruses isolated from infants with and without hearing loss and specific viral genes responsible for this behavior will be characterized. This analysis will include in-vitro replication and viral gene expression in a panel of cell lines and primary cells as a screening assay of viral phenotype. We will also determine if there is an interrelationship between host cell responses and viral gene expression that can be associated with disease phenotype. Finally, the frequency of these gene(s) associated with particular disease phenotype will be defined in a large number of virus isolates from a well characterized population. The proposed research will provide further insight into this process and hopefully, identify markers for the development of SNHL.

Dwight Rouse
Dr. Rouse plans to 1) expand his ongoing patient oriented research activities of a randomized clinical trial of intrapartum chlorhexidine vaginal cleansing. He focuses on clinical trials, i.e., trials in which the intervention to be tested is overlaid on the background of local usual clinical practice, with a minimum of study-related practice constraints, liberal inclusion and few exclusion criteria. The design and conduct of these pragmatic clinical trials poses distinct challenges from devising an implementable intervention to coordinating communication across centers often not otherwise organized into a formal research network. First, the declining patient populations of many academic obstetric units in this country make it difficult to conduct single center trials with adequate sample sizes and expeditious patient accrual. Second, the incidence of some severe but preventable obstetric outcomes (e.g., eclampsia) is quite low, but even for such low incidence conditions, it is often desirable to evaluate interventions which may offer only modest protection. Thus, to achieve adequate statistical power, large sample sizes are necessary. Finally, the effectiveness of an intervention (how it would perform under conditions of actual clinical practice) is an attribute that, in many situations, is as important as its efficacy (how it performs under ideal conditions).

Yingkui Yang
This proposal is directed towards examining the molecular determinants of hMC2R responsible for ligand binding and receptor activation. Based on our previous work with other melanocortin receptors, we hypothesize that: 1) transmembrane domains of hMC2R play important roles in agonist ACTH binding and receptor activation and 2) both extracellular loops and transmembrane domains of hMC2R are crucial for antagonist ASIP binding and activity. To test this hypothesis we will utilize the hMC2R mutagenesis and chimeric receptor studies to determine the molecular basis of hMC2R ligand receptor interaction. The proposed studies will provide important information needed to fill in the gap in our current knowledge of the molecular determinants of hMC2R responsible for ligand binding and receptor activation. The information will serve to establish a foundation on which to build a comprehensive understanding of the signaling events that regulate ACTH mediated adrenal function in physiologic and diseased states.