UC Riverside scientists identify a protein that plays a crucial role in learning and memory.

Iryna Ethyll (left) and Crystal Pontrello, UC Riverside

Biomedical scientists at the University of California, Riverside, have identified a new link between a protein called beta-arrestin and short-term memory that could open new doors for the therapeutic treatment of neurological disorders, particularly Alzheimer’s disease.

Beta-arrestin is expressed in various cells of the body, including cells of the hippocampus, the region of the brain that is involved in learning and the formation of short-term memories. Beta-arrestin, the absence of which impairs normal learning in mice, is one of many “scaffolding proteins” — proteins that support the connections between neurons in the brain.

As our brain develops, new connections called synapses are formed between neurons. In the hippocampus, the formation of synapses is a continuous process. As we learn something new, new connections are formed and some old ones become stronger through a process known as long-term potentiation (LTP). But because brains have only a limited capacity, other old connections must disassemble through a process known as long-term depression (LTD) in order for new synapses to form.

The researchers report online last week in the Proceedings of the National Academy of Sciences that beta-arrestin plays an important role in the plasticity of synaptic connections and LTD by regulating the “actin cytoskeleton,” a dynamic filamentous network of proteins that forms the “backbone” of neurons and is involved in forming new and disassembling old synaptic connections.

“In some pathological conditions such as Alzheimer’s disease, loss of the old synaptic connections far exceeds the formation of new ones, resulting in overall loss of synapses and short-term memory loss,” said Iryna M. Ethell, an associate professor of biomedical sciences and the lead author of the research paper. “Our work, done on mice, shows that if beta-arrestin is removed from neurons, this loss of synapses is prevented.  But we also know that beta-arrestin is required for normal learning and memory; so a fine balance needs to be established. This balance could be easily achieved by pharmaceutical drugs in the future.”

This is the first time researchers anywhere have linked beta-arrestin to Alzheimer’s and learning/memory.

Ethell explained that beta-arrestin can be visualized as energy supplied to a puppeteer (actin cytoskeleton) controlling the strings of the puppets (inter-neuronal connections).  For normal learning to take place, the puppeteer needs to move the strings in a specific order.  But in patients with Alzheimer’s, this supply of energy over-activates and the strings are pulled in a disorderly fashion that results in the strings being broken (loss of synapses) and the puppets collapsing. While the removal of beta-arrestin would prevent this collapse, a complete loss of beta-arrestin would mean no movement of the puppets at all (that is, no learning in the brain), which is equally undesirable.

“A selective tuning of beta-arrestin activity is therefore necessary to partially reduce synapse disassembly,” said Crystal G. Pontrello, the first author of the research paper and a postdoctoral researcher in Ethell’s lab.  “What you want, ideally, is the elimination of only some unused old synaptic connections so that there is room to make new connections.”

Ethell and Pontrello were joined in the research by UC Riverside’s Min-Yu Sun, Alice Lin, Todd A. Fiacco and Kathryn A. DeFea.

The research was supported by a grant to Ethell by the National Institutes of Health.

“This is another, potentially highly efficacious way to block replication of hepatitis C.”

Samuel French, UCLA

Researchers from UCLA’s Jonsson Comprehensive Cancer Center have identified a cell-permeable peptide that inhibits a hepatitis C virus protein and blocks the viral replication that can lead to liver cancer and cirrhosis.

The finding by Dr. Samuel French, a UCLA assistant professor of pathology and senior author of the research, builds on previous work by French’s laboratory that identified two cellular proteins that are important factors in hepatitis C virus infection.

In that earlier research, French and his team set out to identify the cellular factors involved in hepatitis C replication. Using mass spectrometry, they found that heat-shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but the study linked HSP 40 for the first time to hepatitis C infection. The researchers further showed that the natural compound quercetin, which inhibits the synthesis of these proteins, significantly inhibited viral infection in tissue culture.

In the current study, published Jan. 30 in the peer-reviewed journal Hepatology, French and his team demonstrated that the viral, non-structural protein 5A (NS5A) directly binds to HSP 70, and they mapped the site of the NS5A–HSP 70 complex on NS5A. While HSP 70 was previously shown to bind to NS5A in cells, a direct NS5A–HSP70 interaction and complex formation was established in this study. In an effort to stop this interaction, the researchers tested peptides that might inhibit HSP 70.

“This is important because we’ve developed a small peptide which binds to that site and blocks the interaction between the proteins that is important for viral replication,” French said. “This is another, potentially highly efficacious way to block replication of hepatitis C.”

An estimated 160 million people worldwide are infected with hepatitis C, and the conventional treatments — interferon and ribavirin — can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, French said.

“We were surprised that this peptide works this well,” he said. “While its mechanism is different, the activity of this peptide is comparable to other newly developed antivirals.”

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UC Irvine Ph.D. candidate Jesse Catlin wins fellowship for study of how consumers select over-the-counter drugs.

Jesse Catlin, UC Irvine

DayQuil, NyQuil, Advil, Tylenol, Theraflu? Comtrex, Claritin or generic? How does an achy, feverish, congested shopper choose?

Unfortunately, not in a way that demonstrates knowledge of the drugs’ active ingredients, says Jesse Catlin, a doctoral candidate in marketing at UC Irvine’s Paul Merage School of Business. Increasing reports of acetaminophen overdose – a leading cause of acute liver failure in the U.S. – are one result.

Catlin is studying how consumers make decisions about buying and taking over-the-counter medications in an effort to foster more informed choices. His research – conducted through surveys and mock buying exercises in the lab and online – recently earned him a $10,000 Public Impact Fellowship.

Instituted in 2009 by Graduate Division Dean Frances Leslie, the prize supports UCI grad students whose work has the potential to significantly benefit society. Four $10,000 fellowships and 10 honorable-mention awards of $1,000 each are bestowed annually.

“I’ve always been interested in the role that marketing factors like branding, advertising and labeling play in consumers’ health decision making,” says Catlin, who came to UCI with a master’s in economics from California State University, Sacramento.

“Over-the-counter drugs emerged as a particularly intriguing area for research, as these are products people use all the time but about which they seem to know very little. There’s growing concern at the Food and Drug Administration about inadvertent overdoses, and I wanted to learn more about what’s going on in consumers’ minds when making OTC drug decisions.”

His early research results suggest that branding and advertising are far more influential than knowledgeable consideration of active ingredients. Individuals can overdose by taking more than one medication with the same active ingredient at the same time. Many medicines on store shelves contain different combinations of identical ingredients – including acetaminophen.

In addition to causing liver damage, acetaminophen overdoses account for at least 100,000 calls to poison centers and 56,000 emergency room visits annually. And while some of these cases are intentional, more than half are accidental, medical statistics show.

“By better understanding the decision-making process, we can better help people recognize the importance of paying attention to active ingredients in the medications they take,” Catlin says. “Consumers need to know that while OTC products are safe to use as directed, they can have serious adverse effects when misused.”

UC Davis research examines whether the drug Modafinil can improve outcomes for schizophrenia patients.

Michael Minzenberg, UC Davis

Michael Minzenberg, a UC Davis psychiatry researcher, has been awarded a prestigious three-year, $200,000 seed grant from the Dana Foundation to study the brains of patients being treated for schizophrenia to determine how additional treatment to improve cognition interacts with antipsychotic medication.

“Cognition is very important in schizophrenia because it is a strong predictor of outcome. It determines whether a person can be a contributing member of a community, stay out of the hospital and live independently,” said Minzenberg, associate professor in the Department of Psychiatry and Behavioral Sciences and a faculty member of the UC Davis Imaging Research Center.

Schizophrenia is a chronic mental disorder characterized by decline in thought processes and loss of emotional responsiveness. It affects 3.2 million Americans, the majority of whom are not receiving treatment. It can lead to auditory hallucinations, paranoia and delusions.

Despite the importance of cognition in the rehabilitation of those with schizophrenia, there are no U.S. Food and Drug Administration (FDA)-approved drugs for the improvement of cognition in this patient population.

“Dr. Minzenberg is at the forefront of trying to develop therapies for impaired cognition in schizophrenia, using powerful new non-invasive brain imaging to measure the effects of drugs and other treatments on functional networks in the brain,” said Cameron Carter, director of the Center for Neuroscience and the Imaging Research Center at UC Davis.

“His work is suggesting that some of the other medications that patients are taking may interfere with the procognitive effects of some of the newer more promising therapies. If this proves to be true then it will be important to ‘fine tune’ patients’ medications to optimize cognitive outcomes in people with schizophrenia and other brain disorders.”

Modafinil is a drug approved by the FDA for the treatment of narcolepsy. It is also known by the brand name Provigil. Narcolepsy is a chronic neurological disease characterized by sudden urges to sleep, episodes of loss of voluntary muscle tone, vivid dreams while falling asleep or upon awakening, and brief episodes of total paralysis while waking up from sleep. Both genetic and environmental factors appear to contribute to narcolepsy. Although no cure exists, medications can often help restore a patient’s quality of life.

Like other stimulants, Modafinil’s side effects are relatively mild. It is used off-label to combat the effects of sedatives. Currently, it is not prescribed on a long-term basis to schizophrenia patients.

However, Minzenberg and his colleagues conducted a small, unpublished pilot study that showed Modafinil can improve cognition in patients being treated for schizophrenia.

“What we understand about how Modafinil works in the brain leads us to believe that it might be good for improving cognition deficits of our patients,” Minzenberg said.

Because the cause of schizophrenia is unknown, treatment focuses on eliminating symptoms. Antipsychotic drugs are effective at reducing its most serious symptoms: delusions and hallucinations. Any treatment to improve cognition cannot interact with these drugs in a negative way.

“The use of antipsychotic medications is the standard of care in patients with schizophrenia. So, before we can move forward with a large clinical trial involving Modafinil’s impact on cognition, we need to know how it interacts with these drugs.”

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The very action by which the pill works sets off a cellular cascade in other skins cells, according to UCLA researcher.

Antoni Ribas, UCLA

Patients with metastatic melanoma taking the recently approved drug vemurafenib (marketed as Zelboraf) responded well to the twice-daily pill, but some of them developed a different, secondary skin cancer.

Now, researchers at UCLA’s Jonsson Comprehensive Cancer Center, working with investigators from the Institute of Cancer Research in London, Roche and Plexxikon, have elucidated the mechanism by which the drug excels at fighting melanoma but also allows for the development of skin squamous-cell carcinomas.

The very action by which the pill works — blocking the mutated BRAF protein in melanoma cells that spurs the growth and spread of tumors — sets off a cellular cascade in other skin cells (if they have another predisposing cancer mutation) and ultimately accelerates the secondary skin cancers, said Dr. Antoni Ribas, co-senior author of the paper and a UCLA professor of hematology–oncology.

The 18-month study appears in the Jan. 19 edition of the New England Journal of Medicine.

About 50 percent of patients who get melanoma have the BRAF mutation and can be treated with vemurafenib, Ribas said. Of those, approximately one-fourth develop skin squamous-cell carcinomas. In study subjects, the squamous-cell carcinomas were removed surgically, and the use of vemurafenib was not discontinued because of this secondary skin cancer side effect.

“We wondered why it was that we were treating and getting the melanoma to shrink but another skin cancer was developing,” said Ribas, who studies melanoma at the Jonsson Cancer Center. “We looked at what was likely making them grow, and we discovered that the drug was making pre-existing cells with an RAS mutation grow into skin squamous-cell cancers.”

The combined research team performed a molecular analysis to identify the oncogenic mutations in the squamous-cell lesions of patients treated with vemurafenib. Among 21 tumor samples studied, 13 had RAS mutations. In another set of 14 samples, eight had RAS mutations, Ribas said.

“Our data indicate that RAS mutations are present in about 60 percent of cases in patients who develop skin squamous-cell cancers while being treated with vemurafenib,” Ribas said. “This RAS mutation is likely caused by prior skin damage from sun exposure, and what vemurafenib does is accelerate the appearance of these skin squamous-cell cancers, as opposed to being the cause of the mutation that starts these cancers.”

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DoD funds UCSF, Texas A&M collaboration to test therapy that may help people.

Dogs with spinal cord injuries may soon benefit from an experimental drug being tested by researchers at the University of California, San Francisco, and Texas A&M College of Veterinary Medicine & Biomedical Sciences — work that they hope will one day help people with similar injuries.

Funded through a three-year, $750,000 grant from the U.S. Department of Defense, the drug to mitigate damage has already proven effective in mice at UCSF. Now the Texas team will test how it works in previously injured short-legged, long-torso breeds of dog like dachshunds, beagles and corgis, who often suffer injuries when a disk in their back spontaneously ruptures, damaging the underlying spinal cord.

About 120 dogs a year that develop sudden onset hind limb paralysis after such injuries are brought to the Small Animal Hospital of Texas A&M University, where they receive surgical and medical treatment similar to that for human spinal cord injury. Now, researchers will test whether the new treatment works on some of these dogs, with their owners’ consent.

“It would be phenomenal if it works,” said Linda J. Noble-Haeusslein, a professor in the UCSF departments of Neurological Surgery and Physical Therapy and Rehabilitation Science who designed the intervention. “We are in a unique position of being able to treat a dog population where there are simply no current therapies that could effectively improve their hind limb function.”

The new treatment does not seek to regrow injured pathways in the spinal cord. Instead, it aims to mitigate damage secondary to the spinal cord injury. Most spinal cord injuries trigger a cascade of chemical reactions in the spinal cord that collectively damage nearby cells and pathways, contributing to functional deficits including hind limb function.

A few years ago, Noble and her UCSF colleague Zena Werb showed how blocking the action of one protein found in the spinal cord of mammals can help mice recover from spinal cord injuries. This protein, called matrix metalloproteinase-9, can degrade pathways within the cord and cause local inflammation, leading to cell death.

Dog using a medical device to walk.

The injured dogs offer a great opportunity to take the next step on this treatment because their injuries more closely mimic spontaneous human spinal cord injury and, as is the case with humans, no existing treatment has substantially reduced paralysis.

Noble’s co-investigator on the new study, Jonathan Levine, D.V.M., an assistant professor in neurology at Texas A&M University, will treat the dogs through injections of a protein-blocking drug. He will then help the dogs through rehabilitation and assess their recovery. Ongoing studies at UCSF focus on further refining delivery of the drug so as to optimize recovery.

Other researchers have shown that movement can be preserved if as little as 18 percent to 20 percent of the nerve fiber tracts in the spinal cord remain intact.

If successful, the trials in injured dogs may lead to the development of similar treatments for people who suffer spinal cord injuries, Noble said. These are among the most expensive injuries: Every person with an injured spinal cord costs the health care system millions of dollars over his or her lifetime.

Such costs often are overshadowed by the tragic and devastating personal price of the injuries, which dramatically alter lives and most often occur in younger people, with long lives in front of them. According to the National Spinal Cord Injury Statistical Center, based at the University of Alabama, Birmingham, most of the 12,000 Americans who suffer spinal cord injuries are between the ages of 16 and 30.

As of this year, some 265,000 people in the United States are living with such injuries, according to the national center. This includes many wounded soldiers who have returned home from war zones.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Discovery points to possible new target for therapy.

Zena Werb, UC San Francisco

Cancers rarely are deadly unless they evolve the ability to grow beyond the tissues in which they first arise. Normally, cells — even early-stage tumor cells — are tethered to scaffolding that helps to restrain any destructive tendencies. But scientists from the University of Helsinki, Finland, and from UC San Francisco have identified a cleaver-wielding protein that frees some tumor cells, allowing them to further misbehave.

The protein, they discovered, often blankets the surface of breast tumor cells and can help untether the cells from the matrix of their native tissue. Once released, they may continue to expand their numbers into other tissues where their normal counterparts do not tread.

The protein, called hepsin, is a protease, a class of enzymes that cleaves, or cuts, other proteins. Proteases have been targeted successfully by drugs, and hepsin presents a new possible drug target, the researchers said.

“If we could delay or prevent a tumor from switching from one that grows in place to one that invades, then that would be a major milestone in cancer treatment,” said study co-author Zena Werb, a professor of anatomy at UCSF. Werb has for decades studied the ways in which the behavior of tumor cells is influenced by their surroundings, with a focus on breast tumors.

Working with mouse models of breast development and breast cancer in Werb’s UCSF laboratory during a visiting professorship, University of Helsinki scientist Juha Klefström — along with Johanna Partanen, a University of Helsinki graduate student — designed and led experiments that resulted in the discovery of the hepsin protein’s role.

Their findings are published in Monday’s (Jan. 16) edition of the Proceedings of the American Academy of Sciences (PNAS).

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Alliance is UCSF’s third collaboration with Sanofi.

Matthias Hebrok, UC San Francisco

The University of California, San Francisco, has signed an alliance with international pharmaceutical company Sanofi (EURONEXT: SAN and NYSE: SNY) to share expertise in diabetes research and identify drug targets that could lead to new therapies for both type 1 and type 2 diabetes.

The $3.1 million collaboration will bring together scientists in three UCSF labs with deep understanding of the biology of beta cells – insulin-producing cells that are destroyed in type 1 diabetes and often produce too little insulin in type 2 – with Sanofi researchers who are experienced in developing potential drug candidates into actual therapies.

“This is a true partnership between scientists with very different strengths,” said Matthias Hebrok, Ph.D., director of the UCSF Diabetes Center. “UCSF is known for its deep understanding of the underlying biology of diabetes, while Sanofi has great expertise in screening compounds, identifying which molecules have potential, and moving them along to develop a new drug. Such an endeavor is almost impossible to accomplish in a single academic laboratory. Thus, both partners profit from the expertise of the other group.”

The alliance is the university’s third collaboration with Sanofi, alongside brain trauma and oncology research launched last year, since the two signed a master agreement in January 2011 to work together in translating academic science into potential new therapies. Master agreements lay out the fundamental terms of research collaborations, align with the University’s academic mission including broad publication rights, and form part of a core strategy for the UCSF Office of Innovation, Technology and Alliances to expedite that “bench-to-bedside” research.

This also is the first collaboration of its kind for the UCSF Diabetes Center, extending beyond simpler, funded-research agreements to create a two-way partnership in which scientists on both sides contribute technology and expertise to identify drug targets and test their potential.

“Sanofi is pleased to collaborate with the Diabetes Center at UCSF to combine expertise in employing new technologies for the development of innovative diabetes therapies,” said Pierre Chancel, senior vice president in the Diabetes Division at Sanofi. “The potential resulting drug discovery projects will supplement our integrated solutions model for diabetes management and help Sanofi continue to deliver best-in-class solutions to people living with diabetes.”

Together, the team will assess and validate potential drug targets from a UCSF library of roughly 100,000 small interference RNAs (siRNA) – molecules that play a crucial role in turning on and off genes, including the gene that produces insulin. They also will identify Sanofi compounds that might be effective in regulating those molecules, study the impact those compounds have on UCSF laboratory models of diabetes and assess their therapeutic potential.

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UCLA discovery may lead to better understanding of the disease, possible therapies.

John Ringman, UCLA

With a lack of effective treatments for Alzheimer’s, most of us would think long and hard about whether we wanted to know years in advance if we were genetically predisposed to develop the disease. For researchers, however, such knowledge is a window into Alzheimer’s disease’s evolution.

Understanding the biological changes that occur during the clinically “silent” stage — the years before symptoms appear — provides clues about the causes of the disease and may offer potential targets for drugs that will stop it from progressing.

In a new study, researchers at UCLA have identified chemical changes taking place in the brains of people destined to develop familial Alzheimer’s disease at least 10 years before symptoms or diagnoses occur. Reporting in the current online edition of the journal Archives of Neurology, John Ringman, a UCLA associate professor of neurology, and colleagues identified changes in 56 proteins, including increases in the amyloid protein long associated with Alzheimer’s, inflammatory markers and other proteins related to the brain’s synapses, the connections between neurons through which these brain cells communicate with each other.

Familial Alzheimer’s and sporadic, late-onset Alzheimer’s are distinct forms of what many consider a single disease. The majority of Alzheimer’s cases are sporadic and late-onset, developing after age 65; the causes of this disease type are not completely understood but are at least partly genetic. Familial Alzheimer’s (FAD), a rare form of the disease caused by certain gene mutations, affects less than 2 percent of patients. It is typically early-onset, developing before age 65, and it is inherited — all offspring in the same generation have a 50-50 chance of developing FAD if one of their parents had it.

For this study, researchers developed protein profiles drawn from the cerebrospinal fluid of 14 FAD mutation carriers and compared them with five related non-carriers. In all, they identified 56 proteins that showed significant differences between carriers and non-carriers. Fourteen of these proteins had been reported in prior studies on late-onset Alzheimer’s (including APP, transferrin and other inflammatory markers), but many others were unique to this study, including calsyntenin 3, AMPA 4 glutamate receptor and osteopontin. Normally, these proteins are thought to play a role in the growth and remodeling of synapses, and their alteration in pre-symptomatic Alzheimer’s may represent an early manifestation of the loss of these critical structures.

“Unfortunately, we do not yet have effective medications to stop the progression of Alzheimer’s,” said Ringman, who works at UCLA’s Mary S. Easton Center for Alzheimer’s Disease Research. “In this study, we’ve identified chemical changes occurring in the brains of persons destined to develop Alzheimer’s disease 10 years or more prior to the expression of symptoms. By studying the cerebrospinal fluid of persons developing Alzheimer’s disease at a relatively young age with cutting-edge protein chemical techniques, we found changes in markers reflecting inflammation as well as the breakdown of synapses.

“This provides potential new targets for drug interventions, and it helps elucidate the degree to which FAD and late-onset Alzheimer’s are similar and to what degree they are distinct. Such knowledge may ultimately allow us to tailor our treatments to individuals, depending on the ‘type’ of Alzheimer’s they have.”

The study, funded in part by the pharmaceutical company Pfizer Inc., a grant from the state of California and other sources, was performed at UCLA’s Easton Center, one of 10 centers currently receiving funding from the state. State funding helps these centers provide specialized care for patients with Alzheimer’s disease and other forms of dementia and their families, and it enables the centers to provide training for those engaged in the diagnosis and care of patients with dementia in California.

Additional study authors included Gregory Cole, Sophie Sokolow, Karen Gylys, Daniel H. Geschwind, Jeffrey L. Cummings and Hong I. Wan from UCLA; Howard Schulman, Chris Becker and Ted Jones from Caprion Proteomics U.S.; and Yuchen Bai and Fred Immermann from Pfizer Inc.

The Mary S. Easton Center for Alzheimer’s Disease Research at UCLA is part of the UCLA Department of Neurology, which encompasses more than 20 disease-related research programs, along with large clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranked first among its peers nationwide in National Institutes of Health funding (2002-09).

Extending Innovation Network program selects three projects; other academic partners with Roche include UCSF.

Joan Heller Brown, UC San Diego

The new UC San Diego-Roche Extending Innovation Network (EIN) program has been launched with selection of its first three research projects at the University of California, San Diego, School of Medicine. The UC San Diego-Roche EIN program, which was formalized in June 2011, aims to accelerate the discovery of new drug therapies through research innovation at the interface of industry and academia. The program is slated to grow in the coming years as additional rounds of proposals are solicited.

Under this partnership, faculty-initiated research projects are selected for funding from proposals solicited campuswide on a planned biannual basis. The program is headed by a joint steering committee comprising two Roche researchers and two UC San Diego faculty members, Joan Heller Brown, Ph.D., professor and chair of the Department of Pharmacology, and Michael K. Gilson, M.D., Ph.D., professor of pharmacy and pharmaceutical sciences and director of UC San Diego’s new Drug Discovery Institute.

“We are very pleased about this exciting and innovative partnership, which strengthens UCSD Health Sciences’ strategic goal of broadly advancing our programs in drug discovery,” said David A. Brenner, M.D., vice chancellor for health sciences and dean of the UC San Diego School of Medicine.

The EIN program allows Roche to have the first look at in-licensing opportunities that match the company’s strategy, and is designed to further strengthen the cooperation between university research and pharmaceutical development. Other academic institutions that are partners with Roche in the EIN program include Harvard University and UC San Francisco.

The three two-year projects selected in this initial round will use innovative molecular technologies recently developed at UC San Diego to gain a deeper understanding of the mechanisms of neuropsychiatric disease and leukemia, with the ultimate goal of developing effective new treatments.

“This funding will help provide important new opportunities to translate basic discoveries and leading-edge technologies from UC San Diego’s research laboratories into needed therapies for patients — an effort being spearheaded by our new Drug Discovery Institute,” said Palmer Taylor, Ph.D., associate vice chancellor for health sciences and dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences.

The three projects selected for this initial round of funding are as follows.

Xiang-Dong Fu, Ph.D., professor of cellular and molecular medicine and member of the UC San Diego Institute of Genomic Medicine, in collaboration with Michael G. Rosenfeld, M.D., will use cutting-edge genomic and RNA-based approaches to help identify new potential therapeutic targets.  Coupled with a new gene-signature approach, this research project could identify compounds that will ultimately lead to the discovery of new neuropsychiatric drugs.

Paul Insel, Ph.D., professor of pharmacology and medicine, will investigate the expression of the GPCR family of receptors on the surface of cells from patients with chronic lymphocytic leukemia (CLL). There are limited successful therapies for CLL, which is the most common form of adult leukemia and can progress to a very aggressive form that is rapidly lethal.  Insel seeks to identify new targets for drugs to improve the course of this disease.

Gene Yeo, Ph.D., assistant professor of cellular and molecular medicine, will apply innovative technologies to detect abnormal patterns of RNA in neurons and discover molecules that reverse these defects. This work has promise for the treatment of a variety of neuropsychiatric disorders.

Takeda buys Intellikine.

Kevan Shokat, UC San Francisco

A cancer drug company founded by UC San Francisco professor Kevan Shokat, Ph.D., has been acquired by Japan-based Takeda Pharmaceuticals in an effort to add two novel drug projects to Takeda’s pipeline of potential oncology therapies.

Shokat, who chairs the UCSF Department of Cellular and Molecular Pharmacology, launched Intellikine in 2007 to translate his UCSF kinase research into the development of small-molecule drugs. Kinases are enzymes that are known to regulate the majority of cellular pathways. The Intellikine therapies specifically target the PI-3 kinase (PI3K) pathway – a key target in cancer biology due to its impact on a wide array of cellular functions, including cell growth, proliferation and survival.

Intellikine is based on Shokat’s research at UCSF into four common variations of this pathway. In just four years, the company has developed a portfolio of novel small-molecule kinase inhibitors that selectively target the drivers of cancer cell growth and already has moved three potential drugs into human clinical trials. Takeda’s announcement identified two specific drug candidates — INK128 and INK1117 – as being potential “best in class” inhibitors of cancer growth. The third candidate is being developed in partnership with Infinity Pharmaceuticals.

Under the agreement, Takeda America Holdings will purchase Intellikine for $190 million in cash, plus up to $120 million in so-called “BioBucks,” or projected payments linked to specific milestones in clinical development.

Joint BioEnergy Institute researchers develop CAD-type tools for engineering RNA control systems.

Jay Keasling (left) and James Carothers, Berkeley Lab (click image for larger view)

The computer assisted design (CAD) tools that made it possible to fabricate integrated circuits with millions of transistors may soon be coming to the biological sciences. Researchers at the U.S. Department of Energy (DOE)’s Joint BioEnergy Institute (JBEI) have developed CAD-type models and simulations for RNA molecules that make it possible to engineer biological components or “RNA devices” for controlling genetic expression  in microbes. This holds enormous potential for microbial-based sustainable production of advanced biofuels, biodegradable plastics, therapeutic drugs and a host of other goods now derived from petrochemicals.

“Because biological systems exhibit functional complexity at multiple scales, a big question has been whether effective design tools can be created to increase the sizes and complexities of the microbial systems we engineer to meet specific needs,” says Jay Keasling, director of JBEI and a world authority on synthetic biology and metabolic engineering. “Our work establishes a foundation for developing CAD platforms to engineer complex RNA-based control systems that can process cellular information and program the expression of very large numbers of genes. Perhaps even more importantly, we have provided a framework for studying RNA functions and demonstrated the potential of using biochemical and biophysical modeling to develop rigorous design-driven engineering strategies for biology.”

Keasling, who also holds appointments with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California, Berkeley, is the corresponding author of a paper in the journal Science that describes this work. The paper is titled “Model-driven engineering of RNA devices to quantitatively-program gene expression.” Other co-authors are James Carothers, Jonathan Goler and Darmawi Juminaga.

Synthetic biology is an emerging scientific field in which novel biological devices, such as molecules, genetic circuits or cells, are designed and constructed, or existing biological systems, such as microbes, are re-designed and engineered. A major goal is to produce valuable chemical products from simple, inexpensive and renewable starting materials in a sustainable manner. As with other engineering disciplines, CAD tools for simulating and designing global functions based upon local component behaviors are essential for constructing complex biological devices and systems. However, until this work, CAD-type models and simulation tools for biology have been very limited.

Identifying the relevant design parameters and defining the domains over which expected component behaviors are exerted have been key steps in the development of CAD tools for other engineering disciplines,” says Carothers, a bioengineer and lead author of the Science paper who is a member of Keasling’s research groups with both JBEI and the California Institute for Quantitative Biosciences. “We’ve applied generalizable engineering strategies for managing functional complexity to develop CAD-type simulation and modeling tools for designing RNA-based genetic control systems. Ultimately we’d like to develop CAD platforms for synthetic biology that rival the tools found in more established engineering disciplines, and we see this work as an important technical and conceptual step in that direction.”

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