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News Article | May 16, 2017
Site: www.rdmag.com

Researchers from the Sanford-Burnham Preby’s Medical Discovery Institute (SBP) in San Diego have pinpointed the molecule that inhibits the Zika virus, a step towards finding a drug to combat the virus, which has become a global epidemic. “We identified a small molecule that inhibits the Zika virus protease and show that it blocks viral propagation in human cells and in mice,” Alexey Terskikh, Ph.D., associate professor at SBP, said in a statement. “Anti-Zika drugs are desperately needed. “The fact that the compound seems to work in vivo is really promising, so we plan to use it as a starting point to make an even more potent and effective drug.” The researchers used a library of compounds that co-author Alex Strongin, Ph.D., professor at SBP, that had previously shown to inhibit the same compound as the West Nile virus. They also tested other structurally similar molecules available at the SBP’s Conrad Prebys Center for Chemical Genomics to determine whether any also blocked the protease. They were able to identify three promising compounds that were tested for their ability to prevent Zika infection of human brain cells, with the best one also showing the ability to reduce the amount of virus circulating in the blood of Zika-infected mice. “The inhibitor's efficacy in animals is the key to the study's significance,” Terskikh said. “This, and the fact that the compound is likely to be safe make it especially promising. “The compound blocks a part of the protease that's unique to viruses, so it doesn't inhibit similar human proteases. It's also much more potent than previously identified inhibitors of the Zika protease.” Zika is a significant emergent threat to global health, particularly during pregnancy. While it is not life-threatening, Zika has severe health implications beyond microcephaly—a condition where an infant’s head is significantly smaller than what is expected. “Microcephaly is likely just the tip of the iceberg in terms of the potential adverse effects of maternal Zika infection,” Terskikh said. “There may be other, less obvious impacts on brain development that wouldn't be apparent until later. That's something we're also investigating.” Zika despite not being lethal, Zika is considered a global threat because it is spreading rapidly through the Americas, including through parts of the U.S. The researchers are also moving forward with an experimental vaccine that is set to move into phase 2 clinical trials in June. “In addition to a Zika vaccine, we still need antivirals,” Terskikh said. “Some people may be exposed who haven't been vaccinated. “Having a way to treat the infection could help stop Zika from spreading and prevent its sometimes devastating effects.”


News Article | May 16, 2017
Site: www.eurekalert.org

La Jolla, Calif., May 16, 2017 -- New research led by Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), and Alex Strongin, Ph.D., professor at SBP, could be a first step toward a drug to treat Zika infections. Publishing in Antiviral Research, the scientific team discovered a compound that prevents the virus from spreading. "We identified a small molecule that inhibits the Zika virus protease, and show that it blocks viral propagation in human cells and in mice," Terskikh says. "Anti-Zika drugs are desperately needed. The fact that the compound seems to work in vivo is really promising, so we plan to use it as a starting point to make an even more potent and effective drug." The Zika virus has been declared a public health emergency of international concern by the World Health Organization, a rare designation indicating that a coordinated global response is needed. The reason Zika is considered such a threat is that it's spreading rapidly through the Americas, including parts of the U.S., and can cause severe complications. Zika has been linked to an increase in cases of microcephaly, a birth abnormality in which the head and brain are unusually small, and Guillain-Barre syndrome, a rapidly developing neurological condition that causes weakness of the arms and legs and can progress to life-threatening respiratory failure. "Microcephaly is likely just the tip of the iceberg in terms of the potential adverse effects of maternal Zika infection," comments Terskikh. "There may be other, less obvious impacts on brain development that wouldn't be apparent until later. That's something we're also investigating." The scientific team took advantage of a library of compounds that Strongin's lab had previously shown to inhibit the same component of the related West Nile virus. They also tested structurally similar molecules available at the SBP's Conrad Prebys Center for Chemical Genomics (Prebys Center) to determine whether any also blocked the protease. The screening process identified three promising compounds, which were then tested for their ability to prevent Zika infection of human brain cells. The best one of these also reduced the amount of virus circulating in the blood of Zika-infected mice. "The inhibitor's efficacy in animals is the key to the study's significance," Terskikh adds. "This, and the fact that the compound is likely to be safe make it especially promising. The compound blocks a part of the protease that's unique to viruses, so it doesn't inhibit similar human proteases. It's also much more potent than previously identified inhibitors of the Zika protease." This future drug is just one part of the fight against Zika. An experimental vaccine is set to move into phase 2 clinical trials in June. "In addition to a Zika vaccine, we still need antivirals," explains Terskikh. "Some people may be exposed who haven't been vaccinated. Having a way to treat the infection could help stop Zika from spreading and prevent its sometimes devastating effects." This research was performed in collaboration with scientists at the La Jolla Institute for Allergy & Immunology. Funding was provided by the National Institutes of Health (R21NS10047). Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | May 17, 2017
Site: www.sciencedaily.com

New research led by Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), and Alex Strongin, Ph.D., professor at SBP, could be a first step toward a drug to treat Zika infections. Publishing in Antiviral Research, the scientific team discovered a compound that prevents the virus from spreading. "We identified a small molecule that inhibits the Zika virus protease, and show that it blocks viral propagation in human cells and in mice," Terskikh says. "Anti-Zika drugs are desperately needed. The fact that the compound seems to work in vivo is really promising, so we plan to use it as a starting point to make an even more potent and effective drug." The Zika virus has been declared a public health emergency of international concern by the World Health Organization, a rare designation indicating that a coordinated global response is needed. The reason Zika is considered such a threat is that it's spreading rapidly through the Americas, including parts of the U.S., and can cause severe complications. Zika has been linked to an increase in cases of microcephaly, a birth abnormality in which the head and brain are unusually small, and Guillain-Barre syndrome, a rapidly developing neurological condition that causes weakness of the arms and legs and can progress to life-threatening respiratory failure. "Microcephaly is likely just the tip of the iceberg in terms of the potential adverse effects of maternal Zika infection," comments Terskikh. "There may be other, less obvious impacts on brain development that wouldn't be apparent until later. That's something we're also investigating." The scientific team took advantage of a library of compounds that Strongin's lab had previously shown to inhibit the same component of the related West Nile virus. They also tested structurally similar molecules available at the SBP's Conrad Prebys Center for Chemical Genomics (Prebys Center) to determine whether any also blocked the protease. The screening process identified three promising compounds, which were then tested for their ability to prevent Zika infection of human brain cells. The best one of these also reduced the amount of virus circulating in the blood of Zika-infected mice. "The inhibitor's efficacy in animals is the key to the study's significance," Terskikh adds. "This, and the fact that the compound is likely to be safe make it especially promising. The compound blocks a part of the protease that's unique to viruses, so it doesn't inhibit similar human proteases. It's also much more potent than previously identified inhibitors of the Zika protease." This future drug is just one part of the fight against Zika. An experimental vaccine is set to move into phase 2 clinical trials in June. "In addition to a Zika vaccine, we still need antivirals," explains Terskikh. "Some people may be exposed who haven't been vaccinated. Having a way to treat the infection could help stop Zika from spreading and prevent its sometimes devastating effects."


"We're developing tools that will allow us to dig deeper into the science of how the brain works," said Shadi Dayeh, an electrical engineering professor at the UC San Diego Jacobs School of Engineering and the team's lead investigator. "We envision that this nanowire technology could be used on stem-cell-derived brain models to identify the most effective drugs for neurological diseases," said Anne Bang, director of cell biology at the Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Medical Research Institute. The project was a collaborative effort between the Dayeh and Bang labs, neurobiologists at UC San Diego, and researchers at Nanyang Technological University in Singapore and Sandia National Laboratories. The researchers published their work Apr. 10 in Nano Letters. Researchers can uncover details about a neuron's health, activity and response to drugs by measuring ion channel currents and changes in its intracellular potential, which is due to the difference in ion concentration between the inside and outside of the cell. The state-of-the-art measurement technique is sensitive to small potential changes and provides readings with high signal-to-noise ratios. However, this method is destructive—it can break the cell membrane and eventually kill the cell. It is also limited to analyzing only one cell at a time, making it impractical for studying large networks of neurons, which are how they are naturally arranged in the body. "Existing high sensitivity measurement techniques are not scalable to 2D and 3D tissue-like structures cultured in vitro," Dayeh said. "The development of a nanoscale technology that can measure rapid and minute potential changes in neuronal cellular networks could accelerate drug development for diseases of the central and peripheral nervous systems." The nanowire technology developed in Dayeh's laboratory is nondestructive and can simultaneously measure potential changes in multiple neurons—with the high sensitivity and resolution achieved by the current state of the art. The device consists of an array of silicon nanowires densely packed on a small chip patterned with nickel electrode leads that are coated with silica. The nanowires poke inside cells without damaging them and are sensitive enough to measure small potential changes that are a fraction of or a few millivolts in magnitude. Researchers used the nanowires to record the electrical activity of neurons that were isolated from mice and derived from human induced pluripotent stem cells. These neurons survived and continued functioning for at least six weeks while interfaced with the nanowire array in vitro. Another innovative feature of this technology is it can isolate the electrical signal measured by each individual nanowire. "This is unusual in existing nanowire technologies, where several wires are electrically shorted together and you cannot differentiate the signal from every single wire," Dayeh said. To overcome this hurdle, researchers invented a new wafer bonding approach to fuse the silicon nanowires to the nickel electrodes. Their approach involved a process called silicidation, which is a reaction that binds two solids (silicon and another metal) together without melting either material. This process prevents the nickel electrodes from liquidizing, spreading out and shorting adjacent electrode leads. Silicidation is usually used to make contacts to transistors, but this is the first time it is being used to do patterned wafer bonding, Dayeh said. "And since this process is used in semiconductor device fabrication, we can integrate versions of these nanowires with CMOS electronics." Dayeh's laboratory holds several pending patent applications for this technology. Dayeh noted that the technology needs further optimization for brain-on-chip drug screening. His team is working to extend the application of the technology to heart-on-chip drug screening for cardiac diseases and in vivo brain mapping, which is still several years away due to significant technological and biological challenges that the researchers need to overcome. "Our ultimate goal is to translate this technology to a device that can be implanted in the brain." More information: Ren Liu et al, High Density Individually Addressable Nanowire Arrays Record Intracellular Activity from Primary Rodent and Human Stem Cell Derived Neurons, Nano Letters (2017). DOI: 10.1021/acs.nanolett.6b04752


News Article | April 17, 2017
Site: www.nanotech-now.com

Home > Press > 'Neuron-reading' nanowires could accelerate development of drugs for neurological diseases Abstract: A team led by engineers at the University of California San Diego has developed nanowires that can record the electrical activity of neurons in fine detail. The new nanowire technology could one day serve as a platform to screen drugs for neurological diseases and could enable researchers to better understand how single cells communicate in large neuronal networks. "We're developing tools that will allow us to dig deeper into the science of how the brain works," said Shadi Dayeh, an electrical engineering professor at the UC San Diego Jacobs School of Engineering and the team's lead investigator. "We envision that this nanowire technology could be used on stem-cell-derived brain models to identify the most effective drugs for neurological diseases," said Anne Bang, director of cell biology at the Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Medical Research Institute. The project was a collaborative effort between the Dayeh and Bang labs, neurobiologists at UC San Diego, and researchers at Nanyang Technological University in Singapore and Sandia National Laboratories. The researchers published their work Apr. 10 in Nano Letters. Researchers can uncover details about a neuron's health, activity and response to drugs by measuring ion channel currents and changes in its intracellular potential, which is due to the difference in ion concentration between the inside and outside of the cell. The state-of-the-art measurement technique is sensitive to small potential changes and provides readings with high signal-to-noise ratios. However, this method is destructive -- it can break the cell membrane and eventually kill the cell. It is also limited to analyzing only one cell at a time, making it impractical for studying large networks of neurons, which are how they are naturally arranged in the body. "Existing high sensitivity measurement techniques are not scalable to 2D and 3D tissue-like structures cultured in vitro," Dayeh said. "The development of a nanoscale technology that can measure rapid and minute potential changes in neuronal cellular networks could accelerate drug development for diseases of the central and peripheral nervous systems." The nanowire technology developed in Dayeh's laboratory is nondestructive and can simultaneously measure potential changes in multiple neurons -- with the high sensitivity and resolution achieved by the current state of the art. The device consists of an array of silicon nanowires densely packed on a small chip patterned with nickel electrode leads that are coated with silica. The nanowires poke inside cells without damaging them and are sensitive enough to measure small potential changes that are a fraction of or a few millivolts in magnitude. Researchers used the nanowires to record the electrical activity of neurons that were isolated from mice and derived from human induced pluripotent stem cells. These neurons survived and continued functioning for at least six weeks while interfaced with the nanowire array in vitro. Another innovative feature of this technology is it can isolate the electrical signal measured by each individual nanowire. "This is unusual in existing nanowire technologies, where several wires are electrically shorted together and you cannot differentiate the signal from every single wire," Dayeh said. To overcome this hurdle, researchers invented a new wafer bonding approach to fuse the silicon nanowires to the nickel electrodes. Their approach involved a process called silicidation, which is a reaction that binds two solids (silicon and another metal) together without melting either material. This process prevents the nickel electrodes from liquidizing, spreading out and shorting adjacent electrode leads. Silicidation is usually used to make contacts to transistors, but this is the first time it is being used to do patterned wafer bonding, Dayeh said. "And since this process is used in semiconductor device fabrication, we can integrate versions of these nanowires with CMOS electronics." Dayeh's laboratory holds several pending patent applications for this technology. Dayeh noted that the technology needs further optimization for brain-on-chip drug screening. His team is working to extend the application of the technology to heart-on-chip drug screening for cardiac diseases and in vivo brain mapping, which is still several years away due to significant technological and biological challenges that the researchers need to overcome. "Our ultimate goal is to translate this technology to a device that can be implanted in the brain." ### A patent is pending for this technology. Contact Skip Cynar in the campus Innovation and Commercialization Office at or (858) 822-2672 for licensing information. This work was supported by a National Science Foundation CAREER award (ECCS-1351980). The team also acknowledges support from the Center for Brain Activity Mapping at UC San Diego, a Calit2 Strategic Research Opportunities award (CITD137) from the Qualcomm Institute at UC San Diego, a Laboratory Directed Research and Development Exploratory Research Award (LDRD-ER) from Los Alamos National Laboratory, the National Institutes of Health (R21 MH099082), a March of Dimes award and a UC San Diego Frontiers of Innovation Scholar Program award. This work was performed in part at UC San Diego's Nanotechnology Infrastructure, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (grant ECCS-1542148). For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


News Article | April 12, 2017
Site: www.cemag.us

A team led by engineers at the University of California San Diego has developed nanowires that can record the electrical activity of neurons in fine detail. The new nanowire technology could one day serve as a platform to screen drugs for neurological diseases and could enable researchers to better understand how single cells communicate in large neuronal networks. “We’re developing tools that will allow us to dig deeper into the science of how the brain works,” says Shadi Dayeh, an electrical engineering professor at the UC San Diego Jacobs School of Engineering and the team’s lead investigator. “We envision that this nanowire technology could be used on stem-cell-derived brain models to identify the most effective drugs for neurological diseases,” says Anne Bang, director of cell biology at the Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Medical Research Institute. The project was a collaborative effort between the Dayeh and Bang labs, neurobiologists at UC San Diego, and researchers at Nanyang Technological University in Singapore and Sandia National Laboratories. The researchers published their work Apr. 10 in Nano Letters. Researchers can uncover details about a neuron’s health, activity and response to drugs by measuring ion channel currents and changes in its intracellular potential, which is due to the difference in ion concentration between the inside and outside of the cell. The state-of-the-art measurement technique is sensitive to small potential changes and provides readings with high signal-to-noise ratios. However, this method is destructive — it can break the cell membrane and eventually kill the cell. It is also limited to analyzing only one cell at a time, making it impractical for studying large networks of neurons, which are how they are naturally arranged in the body. “Existing high sensitivity measurement techniques are not scalable to 2D and 3D tissue-like structures cultured in vitro,” Dayeh says. “The development of a nanoscale technology that can measure rapid and minute potential changes in neuronal cellular networks could accelerate drug development for diseases of the central and peripheral nervous systems.” The nanowire technology developed in Dayeh’s laboratory is nondestructive and can simultaneously measure potential changes in multiple neurons — with the high sensitivity and resolution achieved by the current state of the art. The device consists of an array of silicon nanowires densely packed on a small chip patterned with nickel electrode leads that are coated with silica. The nanowires poke inside cells without damaging them and are sensitive enough to measure small potential changes that are a fraction of or a few millivolts in magnitude. Researchers used the nanowires to record the electrical activity of neurons that were isolated from mice and derived from human induced pluripotent stem cells. These neurons survived and continued functioning for at least six weeks while interfaced with the nanowire array in vitro. Another innovative feature of this technology is it can isolate the electrical signal measured by each individual nanowire. “This is unusual in existing nanowire technologies, where several wires are electrically shorted together and you cannot differentiate the signal from every single wire,” Dayeh says. To overcome this hurdle, researchers invented a new wafer bonding approach to fuse the silicon nanowires to the nickel electrodes. Their approach involved a process called silicidation, which is a reaction that binds two solids (silicon and another metal) together without melting either material. This process prevents the nickel electrodes from liquidizing, spreading out and shorting adjacent electrode leads. Silicidation is usually used to make contacts to transistors, but this is the first time it is being used to do patterned wafer bonding, Dayeh says. “And since this process is used in semiconductor device fabrication, we can integrate versions of these nanowires with CMOS electronics.” Dayeh’s laboratory holds several pending patent applications for this technology. Dayeh notes that the technology needs further optimization for brain-on-chip drug screening. His team is working to extend the application of the technology to heart-on-chip drug screening for cardiac diseases and in vivo brain mapping, which is still several years away due to significant technological and biological challenges that the researchers need to overcome. “Our ultimate goal is to translate this technology to a device that can be implanted in the brain.” A patent is pending for this technology. Co-authors of the study are Ren Liu, Renjie Chen, Ahmed T. E. Youssef, Sang Heon Lee, Massoud L. Khraiche, John Scott, Yoontae Hwang, Atsunori Tanaka, Yun Goo Ro, Albert K. Matsushita, Xing Dai and Yimin Zhou of UC San Diego; Sandy Hinckley, Deborah Pre and Steven Biesmans of Sanford Burnham Prebys Medical Discovery Institute; Cesare Soci of Nanyang Technological University; and Anthony James, John Nogan, Katherine L. Jungjohann, Douglas V. Pete, and Denise B. Webb of Sandia National Laboratories. This work was supported by a National Science Foundation CAREER award. The team also acknowledges support from the Center for Brain Activity Mapping at UC San Diego, a Calit2 Strategic Research Opportunities award from the Qualcomm Institute at UC San Diego, a Laboratory Directed Research and Development Exploratory Research Award from Los Alamos National Laboratory, the National Institutes of Health, a March of Dimes award and a UC San Diego Frontiers of Innovation Scholar Program award. This work was performed in part at UC San Diego’s Nanotechnology Infrastructure, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation.


News Article | May 4, 2017
Site: www.theengineer.co.uk

Engineers have led a team in the development of nanowires that record the electrical activity of neurons, an advance that could lead to a greater understanding of the brain. The new nanowire technology could eventually act as a platform to screen drugs for neurological diseases and help researchers better understand how single cells communicate in large neuronal networks. “We’re developing tools that will allow us to dig deeper into the science of how the brain works,” said lead investigator Shadi Dayeh, an electrical engineering professor at the University of California San Diego Jacobs School of Engineering. “We envision that this nanowire technology could be used on stem-cell-derived brain models to identify the most effective drugs for neurological diseases,” said Anne Bang, director of cell biology at the Conrad Prebys Center for Chemical Genomics at the Sanford Burnham Medical Research Institute. According to UC San Diego, researchers can uncover details about a neuron’s health, activity and response to drugs by measuring ion channel currents and changes in its intracellular potential, which is due to the difference in ion concentration between the inside and outside of the cell. The measurement technique is sensitive to small potential changes and provides readings with high signal-to-noise ratios. However, this method can break the cell membrane and destroy the cell. It is also limited to analysing one cell at a time, making it impractical for studying large networks of neurons, which are how they are naturally arranged in the body. “Existing high sensitivity measurement techniques are not scalable to 2D and 3D tissue-like structures cultured in vitro,” Dayeh said. “The development of a nanoscale technology that can measure rapid and minute potential changes in neuronal cellular networks could accelerate drug development for diseases of the central and peripheral nervous systems.” The nanowire technology developed in Dayeh’s laboratory is non-destructive and can simultaneously measure potential changes in multiple neurons with the high sensitivity and resolution achieved by the current state of the art. The device is said to consist of an array of silicon nanowires densely packed on a chip patterned with nickel electrode leads that are coated with silica. The nanowires poke inside cells without damaging them and are sensitive enough to measure small potential changes that are a fraction of or a few millivolts in magnitude. Researchers used the nanowires to record the electrical activity of neurons that were isolated from mice and derived from human induced pluripotent stem cells. These neurons survived and continued functioning for at least six weeks while interfaced with the nanowire array in vitro. Another innovative feature of this technology is it can isolate the electrical signal measured by each individual nanowire. “This is unusual in existing nanowire technologies, where several wires are electrically shorted together and you cannot differentiate the signal from every single wire,” Dayeh said. To overcome this hurdle, researchers invented a new wafer bonding approach to fuse the silicon nanowires to the nickel electrodes. Their approach involved silicidation, which is a reaction that binds two solids – silicon and another metal – together without melting either material. This process prevents the nickel electrodes from liquidising, spreading out and shorting adjacent electrode leads. Silicidation is usually used to make contacts to transistors, but this is the first time it is being used to do patterned wafer bonding, Dayeh said. “And since this process is used in semiconductor device fabrication, we can integrate versions of these nanowires with CMOS electronics.” Dayeh’s laboratory holds several pending patent applications for this technology. Dayeh noted that the technology needs further optimisation for brain-on-chip drug screening. His team is working to extend the application of the technology to heart-on-chip drug screening for cardiac diseases and in vivo brain mapping, which is still several years away. “Our ultimate goal is to translate this technology to a device that can be implanted in the brain.” The project was a collaborative effort between the Dayeh and Bang labs, neurobiologists at UC San Diego, and researchers at Nanyang Technological University in Singapore and Sandia National Laboratories. The researchers have published their work – High Density Individually Addressable Nanowire Arrays Record Activity from Primary Rodent and Human Stem Cell Derived Neurons – in Nano Letters.


News Article | February 15, 2017
Site: www.eurekalert.org

La Jolla, Calif., February 15, 2016 (embargoed until 5:00 A.M. EST) -- Biologists have known for decades that enduring a short period of mild stress makes simple organisms and human cells better able to survive additional stress later in life. Now, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have found that a cellular process called autophagy is critically involved in providing the benefits of temporary stress. The study, published today in Nature Communications, creates new avenues to pursue treatments for neurological disorders such as Huntington's disease. Autophagy is a means of recycling cells' old, broken, or unneeded parts so that their components can be re-used to make new molecules or be burned for energy. The process had previously been linked to longevity, in no small part because of research led by Malene Hansen, Ph.D., associate professor at SBP and senior author of the study. The new results suggest that long life and stress resistance are connected at the cellular level. "We used C. elegans--tiny roundworms used to study fundamental biology--to test the importance of autophagy in becoming stress resistant," says Caroline Kumsta, Ph.D., staff scientist in Hansen's lab and lead author of the study. "They're a great model system because they're transparent, so you can easily observe what goes on inside them, most of their genes and molecular signaling pathways have functional counterparts in humans, and they only live a few weeks, which greatly facilitate measuring their lifespans." Kumsta and colleagues incubated worms at 36 °C, significantly above the temperature they are usually kept at in the laboratory, for one hour. After this short heat exposure--a mild form of stress that improves the organism's survival--autophagy rates increased throughout the worms' tissues. When they exposed these heat-primed worms to another, longer heat shock a few days later, worms that were deficient in autophagy failed to benefit from the initial mild heat shock, as observed in heat-primed worms with intact autophagy. The researchers reasoned that a mild heat stress might also improve the worms' ability to handle another condition that worsens with age--buildup of aggregated proteins, which is stressful for cells. To test this hypothesis, Kumsta used worms that model Huntington's disease, a fatal inherited disorder caused by neuronal proteins that start to stick together into big clumps as patients age, leading to degeneration throughout the brain. Exposing worms that make similar sticky proteins in different tissues to a mild heat shock reduced the number of protein aggregates, suggesting that a limited amount of heat stress can reduce toxic protein aggregation. "Our finding that brief heat exposure helps alleviate protein aggregation is exciting because it could lead to new approaches to slow the advance of neurodegenerative diseases such as Huntington's," says Hansen. "The results may also be relevant to Alzheimer's and Parkinson's, which are similarly caused by clumping-prone proteins." "This research raises many exciting questions," adds Hansen. "For example, how does induction of autophagy by a mild heat stress early on make cells better able to survive heat later--what's the cellular memory? There's a lot to follow up on." "A lot of people ask us if this means they should start going to the sauna or do hot yoga," jokes Kumsta. "That may not be an entirely bad idea--epidemiological studies do indicate that frequent sauna use is associated with longer life. But we have a lot more research to do to figure out whether that has anything to do with the beneficial induction of autophagy by heat stress that we see in C. elegans." Kumsta recently received a promotion from postdoc to staff scientist in recognition of her leadership of this study. Financial support for the study was provided by the American Federation for Aging Research and the National Institutes of Health. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | February 27, 2017
Site: www.eurekalert.org

La Jolla, Calif., Feb. 27, 2016 -- Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new regulator of the innate immune response--the immediate, natural immune response to foreign invaders. The study, published recently in Nature Microbiology, suggests that therapeutics that modulate the regulator--an immune checkpoint--may represent the next generation of antiviral drugs, vaccine adjuvants, cancer immunotherapies, and treatments for autoimmune disease. "We discovered that a protein called K-homology splicing regulatory protein (KHSRP) weakens the immune response to viral RNA," says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at SBP, and senior author of the study. "Depleting KHSRP improved immune signaling and reduced viral replication in cell culture and in vivo, suggesting that drugs inhibiting the protein may have therapeutic value." The innate immune response is the first line of defense against pathogens--a one-size-fits-all attack on viruses, bacteria, and pretty much anything that looks like an invader. But innate immunity must be carefully regulated. If the response is too slow or too weak, infections can run rampant, and if the trigger is too sensitive or the response is too strong, excessive inflammation or autoimmune diseases can arise. "That's where KHSRP comes in," explains Chanda. "It physically interacts with a protein called retinoic acid-inducible gene I (RIG-I) to apply the brakes to the innate immune response." RIG-I receptors initiate antiviral immunity by detecting viral RNA in the cytoplasm of cells. When they bind viral RNA, they turn on signaling that leads to the production of interferon, a strong inflammatory signal that helps kill viruses, as well as the induction of other antiviral responses. RIG-I receptors also coordinate signaling with other immune factors to modulate the adaptive immune response--the acquired, specialized response that develops after the innate response and provides long-term immunity. "We identified KHSRP by systematically testing every human proteins to identify those that impact RIG-I signaling," says Stephen Soonthornvacharin, a recent Ph.D. graduate from the Chanda lab. "We found about 240 proteins, but we focused on KHSRP because it was the only one of the 240 that was found to inhibit the very early steps of RIG-I signaling." "Molecules that block KHSRP's actions could serve as adjuvants--components that heighten the immune response--to vaccines against influenza or hepatitis C, as antiviral drugs, or even next-generation cancer immunotherapies," Soonthornvacharin adds. "Also, among the 240 RIG-I regulators we identified, 125 appear to activate RIG-I, so finding drugs that inhibit these proteins may be a way to treat autoimmune conditions involving too much interferon, like type 1 diabetes or lupus. Figuring out which ones are promising requires further investigation." "We think KHSRP protects against autoimmunity," adds Chanda. "RIG-I normally recognizes RNA molecules that arise during viral infections, but it can also mistakenly sense RNA present in normal cells. Without KHSRP, the innate immune response could be erroneously turned on when there's no virus. Increasing the activity of KHSRP might therefore be a way to treat autoimmunity." "Next, we plan to figure out more of the details of how KHSRP regulates RIG-I," says Sunnie Yoh, Ph.D., staff scientist in the Chanda lab and a key contributor to the research. "That's the information that will move us in the direction of developing therapies." This research was performed in collaboration with scientists at the Novartis Research Foundation, the Icahn School of Medicine at Mount Sinai, Oregon State University Corvallis, the Paul Ehrlich Institute in Langen, Germany, and the University of California San Francisco. Financial support was provided by the National Institutes of Health and the James B. Pendleton Charitable Trust. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | December 13, 2016
Site: www.eurekalert.org

La Jolla, Calif., Dec. 13, 2016 - Garth Powis, professor and director of Sanford Burnham Prebys Medical Discovery Institute's (SBP) NCI-designated Cancer Center, has been named a Fellow of the National Academy of Inventors (NAI). Election to NAI Fellow status is a high professional distinction accorded to academic inventors who have demonstrated a prolific spirit of innovation in creating or facilitating outstanding inventions that have made a tangible impact on quality of life, economic development, and the welfare of society. Powis is the Jeanne and Gary Herberger Leadership Chair in Cancer Research at the Institute's Cancer Research Center in La Jolla, CA. Previously he was Professor and Chair, Department of Experimental Therapeutics, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, TX. Powis received his B.Sc. in Biochemistry and Pharmacology from the University of Birmingham, and his D.Phil. in Biochemistry and Pharmacology from Oxford University in the U.K. Powis has been a pioneer in the discovery and translation of novel cancer targets and their small molecule inhibitors as potential cancer therapies. His current research focuses on mechanisms that solid tumors use to adapt and survive in hypoxic environments, escape cell death, form new blood vessels and metastasize. Powis is the author of over 350 peer-reviewed publications and 15 patents, supporting first in class anti-cancer agents, three of which are in clinical trials. They include: PX-12, a thioredoxin inhibitor; PX-866, a phosphatidylinositol-3-kinase inhibitor; and PX-478, an inhibitor of hypoxia inducible factor-1 (HIF-1). He is co-founder of two start-up companies, Prolx Pharmaceuticals, which was acquired by Biomira (now Cascadia), and Phusis Therapeutics. "Dr. Powis exemplifies the innovative and entrepreneurial spirit of faculty and researchers at SBP," said Kristiina Vuori, M.D., Ph.D., president of SBP. "His contributions to cancer research have changed the way cancer treatment has evolved, from systemic chemotherapy to personalized molecularly targeted therapy. On behalf of SBP, I would like to congratulate Dr. Powis for the distinguished honor of being elected as an NAI Fellow." The 175 distinguished academic inventors named today bring the total number of NAI Fellows to 757, representing 229 research universities and governmental and non-profit research institutes. The 2016 Fellows are named inventors on 5,437 issued U.S. patents, bringing the collective patents held by all NAI Fellows to more than 26,000. These academic luminaries have made a significant impact on the economy through innovative discoveries, creating startup companies, and enhancing the culture of academic invention. Included among all NAI Fellows are more than 94 presidents and senior leaders of research universities and non-profit research institutes; 376 members of the three branches of the National Academy of Sciences; 28 inductees of the National Inventors Hall of Fame; 45 recipients of the U.S. National Medal of Technology and Innovation and U.S. National Medal of Science; 28 Nobel Laureates, 215 AAAS Fellows; 132 IEEE Fellows; and 116 Fellows of the American Academy of Arts & Sciences, among other awards and distinctions. Powis will be inducted on April 6, 2017, as part of the Sixth Annual Conference of the National Academy of Inventors at the John F. Kennedy Presidential Library & Museum in Boston, MA. U.S. Commissioner for Patents, Andrew H. Hirshfeld will provide the keynote address for the induction ceremony. In honor of their outstanding accomplishments, Fellows will be presented with a special trophy, medal, and rosette pin. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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