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Examples of UAB IDDRC Research by Project Leaders

Vladimir Parpura
Astrocytes, a subtype of glial cell, exhibit a form of excitability based on intracellular Ca2+ variations. These intracellular calcium variations, i.e., oscillations can be evoked by neurotransmitters. The goal of this research is to test the hypotheses that glutamate release from astrocytes is controlled by the frequency of calcium oscillations and that PKA and PKC modulate calcium-dependent glutamate release from astrocytes. This study will provide new and important information on how astrocytes communicate with neurons. Since astrocytes modulate synaptic transmission by releasing glutamate, this new insight into glial action has potential to change the way we think about central nervous system functions and dysfunctions.

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).

Lucas Pozzo-Miller
The goal of this research is to characterize the functional role of structurally defined neuronal compartments such as spines, dendrites, and presynaptic terminals, and how they participate in synaptic function and plasticity. The work focuses on the transient elevations of intracellular free Ca2+ concentration induced by neuronal activity, and defining their role in synaptic plasticity investigating the effects of neurotrophins on synapses as an initial approach to characterize the regulation of synaptic transmission and plasticity by slow-acting, non-classical neuromodulators. The lab studies the effects of brain-derived neurotrophic factor (BDNF) on dendritic Ca2+ signaling in hippocampal neurons from normal rats, as well as from BDNF or TrkB receptor knockout mice. The modulation of Ca2+ signals in spines and dendrites may underlie the actions of neurotrophic factors in hippocampal synaptic transmission and plasticity. A related project is to characterize the effect of neurotrophic factors on structural differentiation of dendrites, spines and synapses

Kevin Roth
Research in Dr. Roth’s laboratory is focused on the regulation of neuronal apoptosis. Neuronal apoptosis occurs during normal nervous system development and in a variety of neuropathological processes including hypoxic/ischemic injury and neurodegenerative diseases. He has used mice with targeted gene disruptions of specific bcl-2 and caspase family members, in combination with a variety of in vivo and in vitro models of neuronal cell death, to define the cell- and stimulus-specific molecular pathways of cell death. We have demonstrated that normal nervous system development is regulated by APAF-1-, caspase-9-, and caspase-3-dependent apoptosis of neural precursor cells and Bax:Bcl-XL-dependent apoptosis of immature neurons. Neural precursor cell apoptosis also plays an important role in preventing neural tumorigenesis and is triggered by DNA damage. Interestingly, the apoptotic pathway activated by genotoxic injury requires p53, APAF-1, and caspase-9 but neither caspase-3 nor Bax. Ongoing studies suggest that this pathway is important in glial tumorigenesis and that apoptosis avoidance in mutated neural stem cells may lead to brain tumors in adulthood. p53 and Bax were also found to play significant roles in neuronal death triggered by autophagic vacuole formation, a process that can be found in a variety of neurodegenerative diseases. The long-term goals of my laboratory are to define the molecular pathways of apoptotic and autophagic neuronal death during brain development and in neuropathological conditions and to subsequently design pharmacological strategies for affecting the death process. Such studies will yield significant new data on the cellular and molecular regulation of neuronal cell death and hopefully, provide insights into the prevention and treatment of strokes, neurodegenerative diseases and brain tumors.

Robert Schelonka
Studies in a variety of vertebrate species have documented that the ability to respond to specific antigens is acquired in a controlled, stepwise fashion during the development of the fetus, the infant, and the child. Infants and young children are unable to mount an effective humoral immune response against a number of pathogens that offer minimal difficulties to normal adults. Immunologic naiveté, immature patterns of cytokine production and response, and genetic restrictions on the diversity of T cell receptor (TCR) and immunoglobulin repertoires have all been proposed as the mechanisms that underlie the physiologic immunodeficiency of the newborn infant. We propose to test the hypothesis that it is the limitation in the diversity of the T cell and B cell antigen receptor repertoires that serves as the primary determinant in the delayed acquisition of humoral immunity in the newborn infant. The proposed experiments will utilize a murine model wherein either the B cell or the T cell antigen receptor repertoires, or both, can be constrained to mimic major aspects of the neonatal repertoire. The focus is a restriction in the diversity of the third hypervariable region (CDR3) of the IgH chain and the TCR a, b, g, and d chains, which represents a major mechanism of fetal and neonatal repertoire limitation that is shared between human and mouse. The aims of the study are to determine the hierarchy of acquisition of humoral responsiveness to model antigens in adult mice that have received lymphocyte precursors that are constrained to express only fetal-like CDR3 repertoires or prevented from expressing a normal fetal or adult immunoglobulin HCDR3 repertoire, and to delineate the separate roles played by B and T cells in controlling the programmed acquisition of the ability to respond to antigens during ontogeny. Since the mammalian immune system is not completely functional during fetal life, or even at birth, but undergoes a gradual maturation that is ordinarily not complete until some time during the neonatal period, the experiments outlined in this proposal have the potential to answer a number of questions of fundamental significance to the study of humoral immune responsiveness during ontogeny.

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. He is particularly interested in the role of glial cells as K+ and pH buffers and as depository of neuronally-released glutamate. He is studying signals involved in neuron-glial interactions during development, regeneration and myelination. Finally he seeks to identify differences between normal and malignant glial cells. He is using patch-clamp electrophysiology, quantitative ratiometric fluorescence cell imaging and radioisotope flux techniques to study movements of ions across glial cell membranes. He is comparing 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, he 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.