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Tag Archives: proteomics

Friday Science Review: May 28, 2010

A Map to Better Beer? The key signaling protein-protein interactions in yeast have been mapped.  Mass spectrometry was used to discover the global network between protein kinases and phosphatases to generate the “kinome” map, which contains 1844 interactions.  Since yeasts are model organisms with similar signaling pathways as in human cells, this information is relevant for human disease research and drug design.  The data set in this study was so large that the research team created software to store and analyze the data (ProHits) and perform statistical analysis (SAINT).  Dr. Mike Tyers (Samuel Luenefeld Research Institute) is the lead author of the project described in Science magazine.  The entire data set is available at the yeastkinome.org resource website.

Shhhh… Improving Gene Silencing: Micro RNAs (miRNA) control gene expression by interfering with specific RNA transcripts and this requires the Argonaute proteins (AGOs) to perform this function.  Researchers isolated the specific key region in AGO and solved the crystal structure of this segment.  From this, they discovered that there are intricate and specific molecular interactions between the miRNA and AGO that can dictate specificity.  As RNA interference techniques are gaining traction in the therapeutic arena, this discovery may lead to modifications to enhance the effectiveness of these therapies.  Dr. Bhushan Nagar led the McGill University research team and published the findings in Nature or check out this video podcast.

E. coli Survival Switch: The AceK protein in some bacteria acts as a switch responding to stressful environmental cues, allowing the bacteria to bypass the energy-producing Krebs cycle and go into a conservation mode.  Bacteria such as E. coli and Salmonella can survive in low-nutrient environments such as water.  Therefore, the discovery of how AceK works provides a potential target to prevent bacterial contamination in drinking water by inhibiting the ability of the bacteria to go into survival mode.  Dr. Zongchao Jia and postdoctoral fellow Dr. Jimin Zheng at Queen’s University solved the structure of the protein that led to understanding the unique properties of the enzyme in having both phosphorylation and de-phosphorylation activities on the same protein.  This breakthrough is described in the latest edition of Nature.

Little Buggers All Over Us: The Human Microbiome Jumpstart Reference Strains Consortium is trying to catalog all the microbes in the human body.  We are covered by millions and millions of these little critters – as many as 10x more microbes than the number of cells in our body, but they’re not necessarily bad for us.  They actually play important roles in protecting against infection, aid with digestion, developing our immune system and keeping us healthy.  So far, 178 genomes have been sequenced with the goal to sequence around 900 genomes.  The NIH initiated the project and Dr. Michael Surette and his team at the University of Calgary is a major contributor to the study.  The first phase of this initiative is published in Science.

Genomic Modifications in Stem Cells: To further understand stem cells and embryonic development, scientists took a closer look at how the structural organization of genomic DNA (chromatin and histones) plays a role in determining what tissue they become.  They identified and compared specific modifications across the genome that either activates or represses gene expression in different stem cells.  The value of this information is that it suggests differential regulatory mechanisms controlling development and depends on the specific stem cell lineage.  The safety of regenerative medicine lies in these types of studies in basic stem cell biology.  Developmental biologist Dr. Janet Rossant at The Hospital for Sick Children led the study, which appears in the Proceedings of the National Academy of Sciences.  Also, congratulations to Dr. Rossant as a recent recipient of the 2010 Premier’s Summit Award for Medical Research.

Improving Alzheimer Immunotherapy: Delivering antibodies against amyloid-beta peptide (Abeta) directly into the brain is more effective than systemic delivery in reducing amyloid plaques, as demonstrated in a mouse model.  In this novel approach, transcranial focused ultrasound (FUS) was applied to improve permeability of the blood brain barrier without the need for high doses of the antibody.  The researchers administered the therapeutic antibody intravenously along with a contrast agent to follow the progress via MRI imaging.  Using this MRI guided FUS method, they could see the contrast agent enter the brain within minutes and amyloid pathology was improved in the mouse model after four days.  Drs. Kullervo Hynynen and Isabelle Aubert at Sunnybrook Research Institute published their study on-line in PLoS One.

Friday Science Review: December 18, 2009

Advancing Cell Research with Proteomic Tools: Advances in technology – particularly in proteomics – are allowing scientists to perform research in more complex systems, a complexity that more closely reflects the situation inside the body.  In the latest trend, researchers can label two different populations of cells with different modified amino acids and use mass spectrometry to distinguish proteins derived from one population versus the other.  This strategy was recently applied to study the EphB2 receptor protein, which plays an important role in a cell’s communication with an adjacent cell expressing ephrin-B1 protein.  Differential labeling allowed the researchers to determine the unique (and similar) molecular signaling network in each cell population as they coordinate their self-organizational activity.  It’s a powerful tool that can be adapted to investigate various systems that cannot be studied in isolation.  The research was performed in Dr. Anthony Pawson’s group at the Samuel Lunenfeld Research Institute and is published in the journal Science.

New Member in the Protein Synthesis Club: After decades of studying and trying to fully understand the mRNA translational machinery for protein synthesis, new components in this complex process continue to be discovered.  The latest is a protein called DHX29, a helicase enzyme that helps to untangle the nucleic acid during the initiation phase of translation.  Down-regulating the enzyme holds up protein synthesis and presents a possible target point to block cancer cells from growing.  Indeed, when the researchers blocked DHX29 in cancer cells, tumour growth was significantly reduced.  Dr. Nahum Sonenberg was the lead author of the study reported in the early online edition of the Proceedings of the National Academy of Sciences.

PS.  Congratulations to Dr. Sonenberg in becoming the 2009 Researcher of the Year for Biomedical and Clinical Research presented by CIHR.

Low Oxygen Response in Cancer Cells:  Within a large tumour, there may be areas of hypoxic microenvironments – regions that are under low oxygen conditions.  Cells in this environment undergo a stress response to try to adapt by carrying out a process called autophagy.  The consequence of this is that the cancer cells ‘get tough’ and subsequently become resistant to radiation therapy.  This recent study investigated one of the possible cell adaptation methods through activation of the unfolded protein response (UPR) pathway.  Induction of two key proteins, MAP1LC3B and PERK, were required for autophagy.  They also demonstrated that inhibition of autophagy resulted in the cells becoming sensitive to hypoxia and irradiation.  Thus, the molecular players involved in autophagy may be good therapeutic targets.  Dr. Bradly Wouters at the Ontario Cancer Institute led the research and reports the findings in the Journal of Clinical Investigation.

Teasing out the Role of E2f Transcription Factors: Members of the E2f family of transcription factors are key regulators that commit cells through the cell division process.  Information in the literature is somewhat perplexing regarding whether they are essential for this process and different studies will support one argument or the other.  New research settles this debate – at least for the E2f1-3 isoform.  Through a series of expression and deletion studies and looking at the different molecular players involved, it was concluded that E2fs are not absolutely required for normal cell division.  The surprise finding is that E2f1-3 is necessary for cell survival in development and its function switches from ‘activator’ in progenitor cells to ‘repressor’ mode in differentiating cells.  The research was conducted at Toronto Western Research Institute by Dr. Rod Bremner’s team and appears in this week’s Nature journal.  The story is corroborated in another similar study in the same issue.

Possible Risk for Diabetes or Heart Disease: A large genome-wide study revealed an association between a polymorphism in the ARL15 gene (ADP-ribosylation factor-like 15) with lower levels adiponectin.  Adiponectin is a fat cell protein and its circulating level is inversely associated with type 2 diabetes and coronary heart disease.  Accordingly, the polymorphism is also associated to some degree with higher risk of heart disease, diabetes and other metabolic related traits.  Surely this requires a more in depth molecular study but this is a good example of how you can sift through large amounts of data from various genome-wide studies and fish out an important finding.  Dr. Brent Richards, now at McGill University, is the corresponding author of the study published in PLoS Genetics.

Genetic Mutation in Intellectual Disability: Approximately 50% of intellectual disability cases are not related to other syndromes.  In these cases, an explanation for the intellectual disability may lie in the gene called TRAPPC9, where a mutation in the gene causes a truncated form of the protein and renders it inactive.  The research team led by Dr. John Vincent at the Centre for Addiction and Mental Health used microarrays to screen a family that had seven members with non-syndromic intellectual disability to map the TRAPPC9 gene.  Additional families with mutations affecting the same gene validated the importance of TRAPPC9, which encodes proteins involved in the NF-κB signaling pathway.  With this new knowledge, researchers can screen patients or family members to track the mutation and also dig deeper into the mechanisms in the brain that affects cognitive development.  The study appears in the American Journal of Human Genetics.

Friday (the 13th) Science Review: November 13, 2009

No bad luck here in unraveling new genetic and proteomic links in disease…

Gene Variants Linked to Hearing LossA genetic link to hearing loss in children who are being treated with the chemotherapy drug, cisplatin, has been identified.  Cisplatin is a widely used anti-cancer drug but one of the harmful side effects is hearing loss experienced by over 60% of young cancer patients.  In the study by Dr. Michael Hayden’s team (Child & Family Research Institute, Vancouver), they analyzed 220 drug metabolism genes and found variants in two particular genes that are associated to hearing loss in children – one gene is called TPMT (thiopurine methyltransferase) and the other is COMT (catechol-O-methyltransferase).  With this information, doctors can perform genetic tests to determine the patient’s susceptibility to developing hearing loss and seek alternative treatment if necessary.  Further studies investigating how these enzymes contribute to cisplatin-induced hearing loss could lead to drugs to counteract these effects while receiving the benefits of cisplatin therapy.  The study appears in this week’s Nature Genetics.

The Missing Links in 5q- Syndrome: In patients with 5q- syndrome, a portion of chromosome 5 is deleted and the result is abnormal function of bone marrow cells leading to severe anemia.  We now know what is missing in this region of chromosome 5 that have key roles in maintaining the integrity of bone marrow cells.  In the investigation reported in Nature Medicine, Dr. Aly Karsan at the University of British Columbia and BC Cancer Agency discovered that two microRNAs (miRNAs), miR-145 and miR-146a, are lost in 5q- syndrome. MicroRNAs are short, single-stranded RNA that act to down regulate expression of specific target genes.  The targets of miR-145 and miR-146a are two proteins called TIRAP and TRAF6, which play important roles in immune signalling but should be turned off in hematopoietic stem/progenitor cells during blood cell development.  In support of their hypothesis, the researchers demonstrated in mice that forced expression of TRAF6 results in a condition that is similar to human 5q- syndrome.

Cancer Genes Now Linked: Researchers at Queen’s University studying C. elegans worms identified a connection between two genes involved in cancer.  PTEN is a tumour suppressor and loss of function mutations are known to be involved in a number of cancers.  Eph receptor signalling is required in developmental pathways and its expression level is elevated in some cancers.  New evidence now connects PTEN and Eph receptors in development and cancer.  The research led by Dr. Ian Chin-Sang’s team demonstrated an inverse relationship where Eph receptors can phosphorylate and downregulate PTEN.  Conversely, PTEN activity can modulate Eph receptor signaling.  If there is an imbalance in this relationship, then the (negative) effects may be amplified quickly.  The study report appears in the current issue of Developmental Cell.

Determining Thryoid Hormone Receptor Complexes in Yeast: This is a neat genetic array assay using yeast as a simple model system to unravel co-regulators in thyroid hormone receptor (TR) activity.  A yeast strain expressing TR was systematically crossed with each of 384 yeast strains bearing deletions of known genes.  From this unbiased assay, researchers identified four genes that are deemed essential for thyroid hormone function and are also conserved in humans.  Dr. Paul Walfish (Toronto Mount Sinai Hospital) and his team focused on one of these genes, CCR4.  They validated its role in thyroid hormone receptor action by performing a series of CCR4 expression and deletion analyses in cultured human cells and proved its association with TR in response to thyroid hormone.  Details of their findings appear in the early online edition of The Proceedings of the National Academy of Sciences.

FGFR3 Phosphorylation Network in Disease: An emerging field in proteomic studies is large-scale phospho-proteomic analyses using mass spectrometry to map signalling pathways.  This technique was applied to define the FGFR3 phosphorylation network in multiple myeloma and other cancers.  The researchers also demonstrated in their work the ability to quantitatively detect the upregulation or downregulation of over 60 phosphorylation sites on proteins that either responded to growth factor stimulation or inhibition by the pharmacologic drug PD173074.  One could apply this general method for pharmacodynamic monitoring of any drug inhibitor to fully understand its implications in the cell.  Dr. Michael Moran’s research team at the Hospital for Sick Children and University of Toronto published their report in this week’s Proceedings of the National Academy of Sciences.

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