Howard Florey Institute

Howard, United States

Howard Florey Institute

Howard, United States

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Davern P.J.,University of Melbourne | Davern P.J.,Baker IDI Heart and Diabetes Institute | McKinley M.J.,Howard Florey Institute
Brain Research | Year: 2010

Blockade of serotonergic receptors in the lateral parabrachial nucleus (LPBN), via bilateral injections of nonselective 5-hydroxytryptamine (5-HT) 1/2-receptor antagonist, methysergide causes a robust sodium appetite. Our aim was to elucidate which brain regions are activated when serotonergic pathways to the LPBN are blocked and combined with subcutaneous injection of isoproterenol causing a salt appetite. In the experimental group, conscious rats were administered methysergide (4 μg/0.2 μl) injected bilaterally into the LPBN. Control groups included rats administered with injections of vehicle bilaterally into the LPBN, rats administered methysergide into injection sites outside the LPB region, and rats that did not undergo surgery. Each group was treated with a subcutaneous injection of isoproterenol (30 μg/kg), a β-adrenergic agonist, and NaCl and water intakes were measured over 2 h. Bilateral injections of methysergide into the LPBN followed by subcutaneous isoproterenol induced a strong intake of 0.3 M NaCl (p < 0.01) compared with all controls. Greater numbers of c-Fos-positive stained nuclei were observed in all brain regions assessed. The extended amygdala is rich in AT 1 receptors and ablation of these regions has been shown to reduce sodium appetite; therefore, neurons in these sites, and to a lesser extent the lamina terminalis, are likely primary targets of an inhibitory mechanism arising from the LPBN that acts to modulate sodium appetite. © 2010 Elsevier B.V. All rights reserved.


Vihinen M.,University of Tampere | den Dunnen J.T.,Leiden University | Dalgleish R.,University of Leicester | Cotton R.G.H.,Howard Florey Institute
Human Mutation | Year: 2012

Information about genetic variation has been collected for some 20 years into registries, known as locus specific databases (LSDBs), which nowadays often contain information in addition to the actual genetic variation. Several issues have to be taken into account when considering establishing and maintaining LSDBs and these have been discussed previously in a number of articles describing guidelines and recommendations. This information is widely scattered and, for a newcomer, it would be difficult to obtain the latest information and guidance. Here, a sequence of steps essential for establishing an LSDB is discussed together with guidelines for each step. Curators need to collect information from various sources, code it in systematic way, and distribute to the research and clinical communities. In doing this, ethical issues have to be taken into account. To facilitate integration of information to, for example, analyze genotype-phenotype correlations, systematic data representation using established nomenclatures, data models, and ontologies is essential. LSDB curation and maintenance comprises a number of tasks that can be managed by following logical steps. These resources are becoming ever more important and new curators are essential to ensure that we will have expertly curated databases for all disease-related genes in the near future. © 2011 Wiley Periodicals, Inc.


Patent
St. Vincent's Institute and Howard Florey Institute | Date: 2012-08-09

The present invention relates to inhibitors of insulin-regulated aminopeptidase (IRAP) and methods for inhibiting same, as well as compositions comprising said inhibitors. In particular, the inhibitors of the present invention may be useful in therapeutic applications including enhancing memory and learning functions.


Patent
St. Vincent's Institute and Howard Florey Institute | Date: 2013-02-06

The present invention relates to inhibitors of insulin-regulated aminopeptidase (IRAP) and methods for inhibiting same, as well as compositions comprising said inhibitors. In particular, the inhibitors of the present invention may be useful in therapeutic applications including enhancing memory and learning functions.


Walker A.K.,La Trobe University | Walker A.K.,Howard Florey Institute | Walker A.K.,University of Melbourne | Atkin J.D.,La Trobe University | And 2 more authors.
IUBMB Life | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the misfolding and aggregation of distinct proteins in affected tissues, however, the pathogenic cause of disease remains unknown. Recent evidence indicates that endoplasmic reticulum (ER) stress plays a central role in ALS pathogenesis. ER stress activates the unfolded protein response (UPR), a homeostatic response to misfolded proteins. The UPR is initially protective by up-regulation of specific ER stress-regulated genes and inhibition of general protein translation. However, long-term ER stress leads to cell death via apoptotic signaling, thus providing a link to neurodegeneration. Activation of the UPR is one of the earliest events in affected motor neurons of transgenic rodent models expressing ALS-linked mutant superoxide dismutase 1 (SOD1). Recently, genetic manipulation of ER stress in several different SOD1 mouse models was shown to alter disease onset and progression, implicating an active role for the UPR in disease mechanisms. Furthermore, mutations to vesicle-associated membrane protein-associated protein B (VAPB), an ER transmembrane protein involved in ER stress regulation, also cause some cases of familial ALS. ER stress also occurs in spinal cord tissues of human sporadic ALS patients, and recent evidence suggests that perturbation of the ER could occur in ALS cases associated with TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS) and valosin containing protein (VCP). Together these findings implicate ER stress as a potential upstream mechanism involved in both familial and sporadic forms of ALS. © 2011 International Union of Biochemistry and Molecular Biology, Inc.


Tae H.,Howard Florey Institute
Channels (Austin, Tex.) | Year: 2011

The second of three SPRY domains (SPRY2, S1085 -V1208) located in the skeletal muscle ryanodine receptor (RyR1) is contained within regions of RyR1 that influence EC coupling and bind to imperatoxin A, a toxin probe of RyR1 channel gating. We examined the binding of the F loop (P1107-A1121) in SPRY2 to the ASI/basic region in RyR1 (T3471-G3500, containing both alternatively spliced (ASI) residues and neighboring basic amino acids). We then investigated the possible influence of this interaction on excitation contraction (EC) coupling. A peptide with the F loop sequence and an antibody to the SPRY2 domain each enhanced RyR1 activity at low concentrations and inhibited at higher concentrations. A peptide containing the ASI/basic sequence bound to SPRY2 and binding decreased ~10-fold following mutation or structural disruption of the basic residues. Binding was abolished by mutation of three critical acidic F loop residues. Together these results suggest that the ASI/basic and SPRY2 domains interact in an F loop regulatory module. Although a region that includes the SPRY2 domain influences EC coupling, as does the ASI/basic region, Ca2+ release during ligand- and depolarization-induced RyR1 activation were not altered by mutation of the three critical F loop residues following expression of mutant RyR1 in RyR1-null myotubes. Therefore the electrostatic regulatory interaction between the SPRY2 F loop residues (that bind to imperatoxin A) and the ASI/basic residues of RyR1 does not influence bi-directional DHPR-RyR1 signaling during skeletal EC coupling, possibly because the interaction is interrupted by the influence of factors present in intact muscle cells.


Patent
University of Melbourne and Howard Florey Institute | Date: 2010-12-15

The specification relates to methods for treating a neurodegenerative disease such as multiple sclerosis by administering to a subject in need an EphA4 antagonist or an EphA4 ligand antagonist. The antagonist may be a soluble EphA4 or EphA4-binding ephrin or a functional variant thereof such as an EphA4-Fc or an ephrin A5-Fc. The antagonist may be an antibody or an antigen binding fragment, a nucleic acid, polypeptide, peptide, or organic molecule that binds to EphA4 or an EphA4-ligand or a nucleic acid encoding same and downregulates its activity. Combination therapies are also disclosed.


Methods, compositions and kits based on TAM receptors, or TAM receptor ligands or agonists are for detection of neuropathological diseases or determination of their progression. The neural diseases include multiple sclerosis or other inflammatory neural disorders that are characterized by demyelination, oligodendrocyte cytotoxicity and microglial activation. These methods include screening cells of a subject where identification of an elevation of expression of a TAM receptor or a change in expression of a TAM receptor ligand indicates the presence of the disease presence or progression. In addition, subjects with such neuropathological diseases can be treated by administering TAM receptor ligands (such as GAS 6 or Protein S) or by administering agonists such as antibodies specific for the TAM receptors; Axl, Mer or Tyro3.


Patent
Howard Florey Institute | Date: 2014-03-24

The present invention relates generally to the field of therapeutic treatment and compounds having utility therefor, in particular the therapy or management of conditions associated with excessive, unwanted or undesirable sodium ion passage through cellular membranes via voltage-gated sodium channels. In one embodiment the invention is concerned with the treatment of neuropathic pain. The invention contemplates to aryloxy-substituted amines, as sodium channel blockers or modulators. In further embodiments, the invention also relates to compounds which may advantageously have dual sodium channel blocker/modulating and antioxidative (free-radical scavenging) effects. Methods for their manufacture and compositions containing the compounds are also contemplated.


The present disclosure relates to the use of TAM receptor ligands, metabolites, precursor and binding partners thereof in the field of inflammatory neuropathology. This includes the early diagnosis and monitoring of an inflammatory neuropathology as well as screening for medicaments used in the treatment and prophylaxis of such a condition. The method comprises screening blood fluid from a subject for a TAM receptor ligand, or metabolite, or precursor thereof wherein an altered level of the ligand or its metabolite or precursor relative to a control is indicative of the presence of an inflammatory neuropathological disease or condition or a likelihood of developing the same. Diagnostic kits, high throughput screening assays and therapeutic compositions for inflammatory neuropathies are also taught herein.

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