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Examples of UAB IDDRC Research by Project Leaders

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.

Chenbei Chang
The research in Dr. Chang’s laboratory will be focused on the following areas. 1) Regulation of the TGFß signaling during early frog development and in cancer. TGFß (transformation growth factor beta) signals have been implicated in a variety of processes, including cell proliferation, differentiation, migration, and apoptosis. Two main classes of the TGFß ligands, TGFß/Activin/nodal and BMPs, play overlapping and distinct roles during vertebrate embryogenesis and in adult tissues. The activities of these ligands are regulated temporally and spatially by multiple factors. One of the research goals in the lab is to understand how soluble and membrane proteins modulate the TGFß signals, both in development and in cancer formation. Issues related to the presentation of the ligands, the differential activities of different ligands, and the mechanisms of regulation of the TGFß signal transduction by factors such as Twisted Gastrulation and tomoregulin-1 will be studied. 2) Regulation of the EGF receptor-related signaling in development and in cancer. The epidermal growth factor (EGF) signals are amplified in a variety of carcinomas, and the function of the EGF pathway is often opposite to that of the TGFß signals during early cancer formation. The different mechanisms for cross-regulation of the two pathways are not completely understood. Using the frog and the cell culture systems, we aim to study the function of the EGF receptor-related pathways (ErbB pathways) in early vertebrate development and how the ErbB signals may be regulated by factors involved in the TGFß pathway, such as Cripto and tomoregulin-1, during development and in cancer formation. 3) Formation of sensory organs in early frog embryos. Sensory organs (eyes, ears and nose) are primary detection systems for animals to comprehend the environment they live in for survival needs (e.g. food and defense). Despite the importance of the sensory organs, the mechanisms controlling the sensory organ formation are not well understood. One research directions is to investigate the signal pathways and the transcription factors involved in induction and patterning of the sensory placodes in early frog embryos.

Xiaohua Li
The long term goal of the Li laboratory research is to understand the pathophysiology and improve the treatment of behavioral disorders of mood. Based on evidence showing that glycogen synthase kinase-3 (GSK3) is an active and highly regulated protein kinase in neural tissues, GSK3 is an intracellular target of neurotrophins involved in mood disorders, the mood stabilizer lithium inhibits GSK3, and our recent discovered that serotonin, a major mood disorder-related monoamine neurotransmitter, regulates GSK3 in animal brain, we hypothesize that GSK3 is a major protein kinase whose activity can be altered by various neural modulators involved in the development and the treatment of mood disorders. We will test the hypothesis 1) that mood stabilizing agents, including lithium, valproate, and lamotrigine, regulate GSK3 in mouse brain through different mechanisms of action; 2) that serotonergic modulators used in mood disorders, including serotonin reuptake inhibitor antidepressants and dual-acting antipsychotics, regulate GSK3 in mouse brain; and 3) that GSK3 activity is abnormally regulated by altered brain activities that simulate what occur in mood disorders, which can be prevented or reversed by mood disorder treatments. This research should provide significant new insight into the pathophysiology and the treatment of mood disorders.

Guillermo Marqués
Developmental and adult synaptic plasticity, regulation of gene expression during nervous system development, cell signaling and signal transduction by the TGF-ß/BMP pathway in neurons represent targets of projects examining embryonic development cell division and differentiation. Development is under tight genetic control, and mutational analysis in model organisms has proved invaluable to our understanding of the cellular and molecular mechanisms at the core of this process. Of particular interest for both fundamental and practical implications is the development of the nervous system. Cells of ectodermal origin undergo a series of steps that end up in synapse formation, the establishment of specialized structures that allow rapid, reliable communication between the innervating neuron and its target. After the synapse is established it undergoes a process of refinement that results in strengthening or weakening of particular synapses. This synaptic plasticity occurs both during development and in adult life, and is thought to underlie basic nervous systems processes such as learning and memory. Synaptic plasticity during development requires bi-directional communication between the afferent neuron and the target cell, typically another neuron or a muscle. The signaling from target to neuron is known as retrograde signaling, and genetic analysis in the fruit fly Drosophila melanogaster has shown that growth factors of the TGFß family are essential in this process. The projects in the laboratory center on the role of TGFß growth factors in developmental and activity-induced synaptic plasticity. The final goal is understanding molecularly how the post-synaptic cell regulates the efficiency of synaptic transmission, resulting in synapse potentiation or depression and the appropriate behavioral correlate. A combination of genetic, molecular and biochemical approaches are used to this end, and although the favored experimental model is the Drosophila larva neuromuscular junction, other organisms and experimental paradigms are currently being considered.

James Meador-Woodruff
This project is designed to examine the expression of glutamate receptors and related interacting proteins in the thalamus from patients with schizophrenia and a comparison group. The glutamate hypothesis of schizophrenia is supported by pharmacological evidence suggesting involvement of the NMDA receptor, and we have previously demonstrated changes in NMDA receptor stoichiometry in thalamus in this illness. The postsynaptic NMDA receptor complex also includes glutamate receptor interacting proteins that are critical for normal receptor assembly, trafficking, insertion in the plasma membrane, and activation. In addition, colocalization and stimulus specific activation of AMPA receptors are required for initiation of long term potentiation and other NMDA receptor-mediated correlates of neuroplasticity. Thus, we hypothesize that there are abnormalities in the expression of the NMDA and/or AMPA receptors, as well as abnormalities of glutamate receptor interacting proteins associated with the postsynaptic receptor signaling complex in the thalamus in schizophrenia. Accordingly, we will examine the expression of these molecules in postmortem brain samples from schizophrenics and controls. We propose to conduct a detailed examination of functionally linked molecules in the postsynaptic receptor complex, by measuring transcript and protein levels expressed in functionally distinct thalamic nuclei in order to compare changes in mRNA expression by intrinsic GABAergic neurons and glutamatergic relay neurons. These studies will highlight abnormalities that can be more profitably targeted for the generation of novel treatment modalities for this disabling illness.

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.