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Tag Archives: RNAi

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: April 30, 2010

Maybe these primary research projects will lead to the next great “Dendreon” story…

Mirror-rorriM Movement Disorder: Defects in the proper connections between the left and right sides of the brain can lead to involuntary movements where one side of the body follows or mirrors the movement of the other side.  A study of two families affected by inherited cases of mirror movements led to the identification of mutations in the DCC gene (Deleted in Colorectal Carcinoma).  DCC is a receptor for netrin-1, which is a factor that is important for guiding neural axons across the midline to make the proper left-right connections.  This is a key finding in understanding the complexities of how our brains are wired.  Dr. Guy Rouleau (Université de Montréal) and Dr. Frédéric Charron (Institut de recherches cliniques de Montréal) collaborated on the study and is published in the prestigious Science journal.

Improving RNA Therapeutics: RNA interference based therapeutics is gaining traction in the biotech world (eg. Tekmira, Alnylam, MDRNA).  Enhancing the potency of siRNA is the focus of this research study published in Nucleic Acids Research journal.  The technology uses a combination of DNA and RNA analogs to increase the stability of the siRNA agent against nucleases and helps them to evade immune responses that often limit their effectiveness.  Dr. Masad Damha led his group at McGill University.

Also in Montreal, Drs. François Major and Gerardo Ferbeyre (Université de Montréal) announced the launch of the first ribonucleic acid (RNA) engineering laboratory in Canada.  They are using bioinformatics and biochemistry to come up with designer microRNAs that can control the behaviour of RNAs to control or cure cancers.

New Tumour Suppressor:  A recent study demonstrates the tumour suppressor properties of the Cdh11 gene.  The first hint of this function arose from studies showing a frequent loss Cdh11 in retinoblastoma cancers.  Using a series of animal models to determine the role of Cdh11, Dr. Brenda Gallie’s team (Ontario Cancer Institute) demonstrated the tumour suppressor properties of Cdh11 through a mechanism promoting cell death or apoptosis.  The full text article appears online in PLoS Genetics.

Lung Cancer Drug Target: CXCR4 may be the next therapeutic target for treating lung cancer.  Its overexpression in about 10% of lung cancers is associated with poor patient outcome (2.7 vs. 6.1 months survival), likely due to CXCR4’s support for the rapid growth and metastasis of tumours.  On the brighter side, anti-CXCR4 drugs, which are already in existence for the treatment of HIV/AIDS, may be “fast tracked” for testing in lung cancer patients.  Dr. Gwyn Bebb, from the University of Calgary, presented her data recently at the 2nd European Lung Cancer Conference.

Friday Science Review: April 16, 2010

An amazing week of Canadian research advancements…

Cancer Genome Project is Well Underway: The Ontario Institute for Cancer Research (OICR), who is leading the International Cancer Genome Consortium (ICGC), published a report this week in Nature outlining the international effort to sequence 25,000 cancer genomes – 500 genomes from each of the 50 most common cancers such as breast, colon, liver, lung, and pancreatic cancers.  Some partial datasets are already available to the global research community at www.icgc.org.  This is truly a Herculean effort that is only possible because of the international collaborative effort of over 200 members around the globe.  Whole cancer genome sequencing will provide a fundamental base to advance personalized medicine to the next level.  Here is the original OICR press release and you can read a more comprehensive ‘Scientific American’ style news feature article on the cancer genome project here in the same issue of Nature.

Seek and Destory: Non-Hodgkins lymphoma cancer is taking a big hit from a newly discovered compound that destroys lymphoma cells.  The small molecule compound targets and blocks a transcription factor called BCL6, which is responsible for half of non-Hodgkins lymphoma cases.  Scientists started with the 3D structure of the BCL6 protein and used computer-aided drug design to perform in silico screening of over a million compounds.  They eventually narrowed it down to this one compound that proved to be efficacious and also non-toxic.  Dr. Gilbert Prive at the University Health Network led the innovative project that demonstrates the success of a computational approach to drug design and the ability to target transcriptions factors with minimal side effects.  Read all about it! – in the free full text article in Cancer Cell.

Divide and Conquer: Cell division is a complicated process with the synchronized dance of chromosomes segregating to each new cell.  It is a poorly understood process but research is this field is advancing with the discovery of new essential proteins involved in cell divisionDr. Laurence Pelletier (Samuel Lunenfeld Research Institute) and his collaborators in Europe used a combination of RNAi tools and mass spectrometry techniques to identify the components of protein complexes involved in cell division.  As cancer cells are hyperactive dividing cells, this new information will also aid in the advancement of cancer targeting therapeutics.  The study appears in the journal Science.

The Missing Link: Many have suspected that there must be some link or relationship between stress, anxiety and depression.  Now there is molecular evidence that this is true.  The connection involves the interaction between corticotropin releasing factor receptor 1 (CRFR1) and certain types of serotonin receptors (5-HTRs).  CRFR1 activity leads to stress related anxiety and it also stimulates an increase in the number of 5-HTRs in the brain, which can lead to signaling abnormalities causing depression.  The team headed by Dr. Stephen Ferguson at the University of Western Ontario also developed a small molecule inhibitor that blocks 5-HTRs.  Let’s hope this inhibitor and knowledge of the molecular links lead to more effective treatments for these disorders.  Check out the free full-text article in Nature Neuroscience.

Smart Buggers:  Understanding how bacteria become resistant to last-resort antibiotic drugs just got a boost from a McMaster University study.  Vancomycin resistant methicillin-resistant staphylococcus aureus (VMRSA), also known as the hospital superbug, is a rapidly growing problem with limited effective solutions.  The research team identified the histidine kinase VanSsc protein as the direct vancomycin detector in bacteria, which then triggers the expression of three genes that provide the drug resistance.  This is the first important step in redesigning antibiotic drugs to effectively fight these little buggers.   Dr. Gerry Wright and his collaborators published their exciting work in Nature Chemical Biology.

Not Just a Bad Golf Shot: Scientists have identified mutations in the SHANK3 gene that are associated with schizophrenia.  SHANK3 is a scaffolding protein involved in the formation of the synapse and maintains the structure of nerve cells.  Dr. Guy Rouleau’s team at the Université de Montréal discovered the new mutations (R1117X and R536W) in two families with schizophrenia patients where one of these families had three affected brothers.  Further molecular and genetic studies in zebrafish models confirmed that the R1117X mutation causes behavioural defects.  Earlier studies linked SHANK3 mutations to autism, which suggests that there is a molecular connection between the two neurological disorders.  The findings are reported in this week’s edition of the Proceedings of the National Academy of Sciences.

Gene Therapy is Still Alive: The promise of gene therapeutics to cure diseases may not have lived up to the hype presented a decade ago but there are still some hopeful successes using gene therapy.  One recent example comes from Laval University where researchers repaired the defective dystrophin gene responsible for Duchenne muscular dystrophy (DMD). In some cases of DMD, the dystrophin gene is misread causing a frame-shift mutation.  These frame-shift mutations may be targeted and repaired by enzymes called meganucleases.  A proof-of-principle project by Dr. Jacques Tremblay demonstrated that expression of specific meganucleases in the muscle of a DMD mouse model can restore the normal reading frame of a mutated dystrophin gene.  More details in this week’s edition of Gene Therapy.

Friday Science Review: January 22, 2010

Some really exciting research in this week’s review…

Special (RNAi) Delivery: One of the obstacles for RNAi based therapeutics is the difficulty in getting the RNAi into the cells efficiently to invoke a positive response.  Vancouver based Tekmira Pharmaceuticals (TSX: TKM.TO), in partnership with Alnylam Pharmaceuticals (Nasdaq: ALNY) and researchers at the University of British Columbia, Drs. Pieter Cullis and Marco Ciufolini, developed a new and improved RNAi delivery method that is 10X better than their standard delivery platform.  Using their knowledge of lipid structure and how specific features influences delivery into cells, they used a rational design approach to develop a new cationic lipid, DLin-KC2-DMA (KC2), that is used with their current SNALP system (stable nucleic acid-lipid particles) to achieve the remarkable results.  Details of the study are reported in this week’s issue of Nature Biotechnology.

Resolving Stem Cell Populations: The differentiation of stem cells is a complex multi-step process that is not fully understood.   With each step, the potential of that stem cell becomes more and more restricted.  Researchers performed a series of intricate detailed studies on cell populations to resolve distinct Intermediate Term Reconstituting Hematopoietic Stem Cells or ITRC (versus long- and short-term populations).  The significance of this key finding is that researchers who are interested in harnessing the potential of long-term reconstituting hematopoietic stem cells can more accurately study a pure population of true, self-renewing stem cells with homogeneous characteristics.  Prior to this new “intermediate-term” identification, the majority of “long-term” cells were actually comprised of intermediate-term cells.  Dr. Norman Iscove and his team at the University Health Network describe their work in the latest issue of Cell Stem Cell.

Fishing for New Drugs: A high-throughput behavioural monitoring system to observe the response of Zebrafish to neuroactive chemical compounds should help expedite the discovery of new drugs for neurological disorders.  Researchers setup a video system and applied “behavioural barcodes” that they say can track the effects of 14,000 chemicals on zebrafish behaviour.  The capacity of this large-scale screen is unique and the use of zebrafish is quite informative because they are transparent, genetically tractable, and more similar to humans than you might think.  In this platform, response to two strong light pulses after exposure to chemicals is monitored and the observations are translated into barcodes that make data analysis of this magnitude a lot more manageable.  Drs. Jennifer Bryan and Rick White at UBC collaborated with Harvard researchers and published their study in Nature Chemical Biology.

Intrinsic Stimulator of Muscle Regeneration: A new subpopulation of cells in muscle tissue that contribute to muscle injury repair has been identified.  The surprise is that these cells, called fibro/adipogenic progenitors (FAPs), are derived from a different developmental lineage as muscle cells.  These fat-lineage cells, which are resident in muscle tissue, are ‘activated’ in response to muscle damage but they do not become muscle cells.  Instead, they release factors that promote and enhance muscle progenitors in the myogenesis repair process.  The conundrum, however, is that too much of these FAPs can lead to fibrosis and contribute to muscle disorders.  The study, reported in Nature Cell Biology, was led by Dr. Fabio Rossi at the University of British Columbia.

Pharmacoviral Therapy for Gliomas: Oncolytic viruses (VSVs) are used in the treatment against malignant gliomas but are limited in efficacy due to the viral induced IFN (interferon) response – one of our body’s natural defense mechanism.  Knowledge of the molecular mechanisms involving the mTOR pathway in IFN production led researchers to investigate the use of rapamycin, an mTOR inhibitor, in conjunction with the VSVs.  This “pharmacoviral” combinatorial approach was very successful when tested in rats with malignant gliomas and represents a potentially new therapeutic strategy.  Dr. Nahum Sonenberg and his team at McGill University are experts in the mTOR pathway and describe their work in the Proceedings of the National Academy of Sciences.

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