Belinda Cairns
Genentech
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Publication
Featured researches published by Belinda Cairns.
Journal of Clinical Investigation | 1999
Nicholas van Bruggen; Harold Thibodeaux; James T. Palmer; Wyne P. Lee; Ling Fu; Belinda Cairns; Daniel Tumas; Robert Gerlai; Simon-Peter Williams; Menno van Lookeren Campagne; Napoleone Ferrara
VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability. VEGF causes extravasation of plasma protein in skin bioassays and increases hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen tension triggers VEGF expression, and increased protein and mRNA levels for VEGF and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain edema, provoked in part by enhanced cerebrovascular permeability, is a major complication in central nervous system pathologies, including head trauma and stroke. The role of VEGF in this pathology has remained elusive because of the lack of a suitable experimental antagonist. We used a novel fusion protein, mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient cortical ischemia followed by reperfusion. Using high-resolution magnetic resonance imaging, we found a significant reduction in volume of the edematous tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12 weeks after treatment, measurements of the resultant infarct size revealed a significant sparing of cortical tissue. Regional cerebral blood flow was unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders.
Journal of Cerebral Blood Flow and Metabolism | 2001
Simon P. Green; Belinda Cairns; Julie Rae; Carol Errett-Baroncini; Jo-Anne Hongo; Richard W. Erickson; John T. Curnutte
Gp91-phox is an integral component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex that generates reactive oxygen species (ROS) in activated circulating phagocytes. The authors previously demonstrated that gp91-phox knockout (KO) mice show significant protection from neuronal injury after cerebral ischemia–reperfusion injury, suggesting a pivotal role for this enzyme. Moreover, results from chimeric mice suggested that elimination of gp91-phox from both circulating phagocytes and a putative central nervous system (CNS) source were required to confer neuroprotection. In the current study, the authors demonstrated gp91-phox–specific immunostaining of perivascular cells in the CNS of control rats. However, after transient cerebral ischemia, gp91-phox–positive phagocytes were observed within the core ischemic region and activated microglial cells were positive in the penumbra. Such activated microglial cells were also gp91-phox–positive in the CNS of a chimpanzee with mild meningitis. Finally, in humans, both normal adult CNS tissues and isolated fetal microglial cells expressed gp91-phox mRNA. These microglia also expressed mRNA for the five other known components that comprise the NADPH oxidase complex. These data strongly suggest that microglial cells may contain a functionally active NADPH oxidase capable of generating ROS during CNS inflammation.
Experimental Brain Research | 1998
Robert Gerlai; Simon Williams; Belinda Cairns; Nicholas van Bruggen; Paul Moran; Ai Shih; Ingrid W. Caras; Hans Sauer; Heidi S. Phillips; John W. Winslow
Abstract Gene targeting using homologous recombination in embryonic stem (ES) cells offers unprecedented precision with which one may manipulate single genes and investigate the in vivo effects of defined mutations in the mouse. Geneticists argue that this technique abrogates the lack of highly specific pharmacological tools in the study of brain function and behavior. However, by now it has become clear that gene targeting has some limitations too. One problem is spatial and temporal specificity of the generated mutation, which may appear in multiple brain regions or even in other organs and may also be present throughout development, giving rise to complex, secondary phenotypical alterations. This may be a disadvantage in the functional analysis of a number of genes associated with learning and memory processes. For example, several proteins, including neurotrophins – cell-adhesion molecules – and protein kinases, that play a significant developmental role have recently been suggested to be also involved in neural and behavioral plasticity. Knocking out genes of such proteins may lead to developmental alterations or even embryonic lethality in the mouse, making it difficult to study their function in neural plasticity, learning, and memory. Therefore, alternative strategies to gene targeting may be needed. Here, we suggest a potentially useful in vivo strategy based on systemic application of immunoadhesins, genetically engineered fusion proteins possessing the Fc portion of the human IgG molecule and, for example, a binding domain of a receptor of interest. These proteins are stable in vivo and exhibit high binding specificity and affinity for the endogenous ligand of the receptor, but lack the ability to signal. Thus, if delivered to the brain, immunoadhesins may specifically block signalling of the receptor of interest. Using osmotic minipumps, the protein can be infused in a localized region of the brain for a specified period of time (days or weeks). Thus, the location and timing of delivery are controlled. Here, we present methodological details of this novel approach and argue that infusion of immunoadhesins will be useful for studying the role particular receptors play in behavioral and neural plasticity.
Techniques in The Behavioral and Neural Sciences | 1999
Robert Gerlai; Natasha Shinsky; A. Shih; P. Williams; Jane Winer; Mark Armanini; Paul Moran; Belinda Cairns; John W. Winslow; Wei-Qiang Gao; Heidi S. Phillips
Publisher Summary This chapter describes application of immunoadhesins, perhaps most relevant for the behavioral neuroscientist. It focuses on a particular protein family (EphA receptor tyrosine kinases) and the investigation of their potential role in certain aspects of behavior and brain function. The chapter is intended to be an example to delineate the advantages along with the disadvantages of using immunoadhesins, a method novel in behavioral neuroscience. In addition, the present findings revealed a role for EphA receptor tyrosine kinases in cognitive function in the adult mammalian brain. These findings open an unexpected avenue into the functional analysis of this large receptor protein family and may lead to novel targets for therapeutic intervention in human brain and behavioral disorders. They also demonstrate that protein targeting with the application of immunoadhesins may be a useful research strategy in the analysis of molecular components involved in such complex behavioral traits as learning and memory.
Proceedings of the National Academy of Sciences of the United States of America | 1999
Menno van Lookeren Campagne; Harold Thibodeaux; Nick van Bruggen; Belinda Cairns; Robert Gerlai; James T. Palmer; Simon Williams; David G. Lowe
The Journal of Neuroscience | 1999
Robert Gerlai; Natasha Shinsky; A. Shih; P. Williams; J. Winer; Mark Armanini; Belinda Cairns; John W. Winslow; Wei-Qiang Gao; Heidi S. Phillips
The Journal of Neuroscience | 2000
Menno van Lookeren Campagne; Harold Thibodeaux; Nick van Bruggen; Belinda Cairns; David G. Lowe
Archive | 2004
Belinda Cairns; Ruihuan Chen; Gretchen Frantz; Kenneth J. Hillan; Hartmut Koeppen; Heidi S. Phillips; Paul Polakis; Susan D. Spencer; Victoria Smith; P. Mickey Williams; Thomas D. Wu; Zemin Zhang; Chie Sakanaka; Anan Chuntharapai; Chae Reed
Archive | 2007
Belinda Cairns; Ruihuan Chen; Gretchen Frantz; Kenneth J. Hillan; Hartmut Koeppen; Heidi S. Phillips; Paul Polakis; Susan D. Spencer; Victoria Smith; P. Mickey Williams; Thomas D. Wu; Zemin Zhang
Archive | 2002
Belinda Cairns; Ruihuan Chen; Gretchen Frantz; Kenneth J. Hillan; Hartmut Koeppen; Heidi S. Phillips; Paul Polakis; Victoria Smith; Susan D. Spenser; Mickey P. Williams; Thomas D. Wu; Zemin Zhang