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Wang X.,California Institute for Biomedical Research
Frontiers in Immunology | Year: 2015

The phosphoinositide 3-kinase (PI 3-kinase, PI3K) pathway transduces signals critical for lymphocyte function. PI3K generates the phospholipid PIP3 at the plasma membrane to recruit proteins that contain pleckstrin homology (PH) domains - a conserved domain found in hundreds of mammalian proteins. PH domain-PIP3 interactions allow for rapid signal propagation and confer a spatial component to these signals. The kinases Akt and Itk are key PI3K effectors that bind PIP3 via their PH domains and mediate vital processes - such as survival, activation, and differentiation - in lymphocytes. Here, we review the roles and regulation of PI3K signaling in lymphocytes with a specific emphasis on Akt and Itk. We also discuss these and other PH domain-containing proteins as they relate more broadly to immune cell function. Finally, we highlight the emerging view of PH domains as multifunctional protein domains that often bind both lipid and protein substrates to exert their effects. © 2015 Wang, Hills and Huang.


Wang F.,Scripps Research Institute | Wang F.,California Institute for Biomedical Research | Ekiert D.C.,Scripps Research Institute | Ahmad I.,Scripps Research Institute | And 11 more authors.
Cell | Year: 2013

Some species mount a robust antibody response despite having limited genome-encoded combinatorial diversity potential. Cows are unusual in having exceptionally long CDR H3 loops and few V regions, but the mechanism for creating diversity is not understood. Deep sequencing reveals that ultralong CDR H3s contain a remarkable complexity of cysteines, suggesting that disulfide-bonded minidomains may arise during repertoire development. Indeed, crystal structures of two cow antibodies reveal that these CDR H3s form a very unusual architecture composed of a β strand "stalk" that supports a structurally diverse, disulfide-bonded "knob" domain. Diversity arises from somatic hypermutation of an ultralong DH with a severe codon bias toward mutation to cysteine. These unusual antibodies can be elicited to recognize defined antigens through the knob domain. Thus, the bovine immune system produces an antibody repertoire composed of ultralong CDR H3s that fold into a diversity of minidomains generated through combinations of somatically generated disulfides. © 2013 Elsevier Inc.


JUPITER, FL, Feb. 14, 2017 - A pair of scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded up to $3.3 million from the National Cancer Institute of the National Institutes of Health (NIH) to create the next generation of breast cancer treatments for the thousands of patients whose current treatment options are limited. Ben Shen, TSRI professor and co-chair of the Department of Chemistry, and Christoph Rader, TSRI associate professor in the Department of Immunology and Microbiology, will co-lead the new five-year study. The researchers aim to develop a potent type of therapy known as an antibody-drug conjugate (ADC). This new class of anti-cancer drugs combines the specificity of antibodies, which attack only cells they recognize, with a highly toxic payload designed to kill specific cancer cells with far greater efficiency than most currently available treatments. So far, only three of these combination therapies have been approved by the U.S. Food and Drug Administration (FDA). The new ADC approach targets HER2-postive and ROR1-positive breast cancers, which are often aggressive and harder to treat with conventional chemotherapy and hormone drugs. The new grant builds on the work done in both the Shen and Rader labs. Shen and his colleagues recently uncovered a new class of natural products called tiancimycins, (TNMs) which kill selected cancer cells more rapidly and more completely compared with the toxic molecules already used in FDA-approved ADCs. Rader, who has spent most of his scientific career at TSRI and the NIH, has been studying and developing site-specific ADCs to treat cancer. "This grant matches my lab's work on advancing antibody engineering and conjugation technologies with the world-class natural product-based drug discovery in Ben Shen's lab," Rader said. "It's precisely what I came to Scripps Florida for: to build new molecules at the interface of chemistry and biology that can advance medicine. I'm very pleased that the NIH continues to invest in our ideas." Since HER2 and ROR1 expression is highly complementary, the new collaboration could provide new treatment options for at least 50 percent of breast cancer patients, Shen noted. "At Scripps Florida we not only do great science, but we have even greater opportunities to collaborate on projects like this," Shen added. "The combination of Christoph Rader's antibody technology and the tiancimycins, which have been proven to be exquisitely potent, should produce an antibody drug conjugate that we hope to move very quickly into the clinic." The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


LA JOLLA, CA - February 22, 2017 - The MagnaSafe Registry, a new multicenter study led by scientists at The Scripps Research Institute (TSRI), has demonstrated that appropriately screened and monitored patients with standard or non-MRI-conditional pacemakers and defibrillators can undergo MRI at a field strength of 1.5 tesla without harm. These devices are not presently approved by the U.S. Food and Drug Administration (FDA) for MRI scanning. The researchers observed no patient deaths, device or lead failures, losses of pacing function or ventricular arrhythmias in 1,500 patients who underwent MRI using a specific protocol for device interrogation, device programming, patient monitoring and follow-up designed to reduce the risk of patient harm from MRI effects. The research will be published as an Original Article in the February 23, 2017 issue of The New England Journal of Medicine. The use of MRI poses potential safety concerns for patients with an implanted cardiac device. These concerns are a result of the potential for magnetic field-induced cardiac lead heating, which could result in cardiac injury and damage to an implanted device. As a result, it has long been recommended that patients with a pacemaker or defibrillator not undergo MRI scanning, even when MRIs are considered the most appropriate diagnostic imaging method for their care. Despite the development of devices designed to reduce the potential risks associated with MRI, a large number of patients have devices that have not been shown to meet these criteria and are considered "non-MRI-conditional." At least half these patients are predicted to have the need for MRI after a device has been implanted. Researchers established the MagnaSafe Registry to determine the frequency of cardiac device-related events among patients with non-MRI-conditional devices, as well as to define a simplified protocol for screening, monitoring and device programming before MRI. "Given the great clinical demand for MRI for patients with a standard pacemaker or defibrillator, we wanted to determine the risk," said study leader Dr. Robert Russo, an adjunct professor at TSRI and director of The La Jolla Cardiovascular Research Institute. In the MagnaSafe Registry, researchers at 19 U.S. institutions tested 1,000 cases with a non-MRI-conditional pacemaker (one not approved for use in an MRI) and 500 cases of patients with a non-MRI-conditional implantable cardioverter defibrillator (ICD), a device that can shock the heart in response to a potentially fatal cardiac rhythm. They scanned regions other than the chest, such as the brain, spine or extremities--where MRI is traditionally the best option for imaging. The researchers tested the devices at an MRI field strength of 1.5 tesla, a standard strength for MRI scanners and reprogrammed some devices according to a prespecified protocol for the MRI examination. "If the patient was not dependent upon their pacemaker, the device was turned off," explained Russo. "If they could not tolerate having the device turned off, it was set to a pacing mode that did not sense cardiac activity. The reason was that the pacemaker could sense the electrical activity (radiofrequency energy) from the MRI scanner and the function of the device could be inhibited, which could be catastrophic if you depend upon your pacemaker for your heartbeat." Russo and his co-investigators did observe adverse effects in a small group of patients. Six patients had a brief period of atrial fibrillation, and in six additional cases pacemaker partial reset (a loss of stored patient information) was noted. But in no cases did the researchers observe device failure or a failure in the leads that connect the device to the heart when the protocol was followed. "One ICD generator could not be interrogated after MRI and required immediate replacement; the device had not been appropriately programmed per protocol before the MRI," explained Russo. These findings led the researchers to conclude that "device removal and replacement seem unlikely to be safer than proceeding with scanning for patients with a pacemaker or an ICD who require a nonthoracic MRI," provided a protocol similar to the MagnaSafe protocol was followed. "Patients with a standard or non-MRI-conditional pacemaker can undergo clinically indicated MRI without harm if a protocol such as the 'MagnaSafe' protocol used in this study is followed and patients are screened and monitored as described," said Russo. The researchers also noted that their results may not be predictive of findings with all device and lead combinations, higher MRI field strengths, patients younger than 18 years of age and MRI examinations of the chest or cardiac resynchronization devices (those designed to increase the function of a failing heart). The researchers plan to follow up by studying the risk for patients in need of a chest scan at scanner field strength of 1.5 tesla, as well as an MRI of any anatomic area at a higher field strength (3.0 tesla). The study, "Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator," also included authors from the University of California, San Diego; Scripps Memorial Hospital; the University of California, Los Angeles; Providence St. Joseph Medical Center; the University of Arizona; Intermountain Medical Center; Inova Heart and Vascular Institute; Allegheny General Hospital; Abington Memorial Hospital; Yale University School of Medicine; Providence Heart Institute; Oklahoma Heart Institute; the University of Mississippi Medical Center; the Medical College of Wisconsin; Bassett Medical Center; Carnegie Hill Radiology; Methodist DeBakey Heart and Vascular Center and Baptist Health. The study was supported by grants from St. Jude Medical, Biotronik, Boston Scientific and the Hewitt Foundation for Medical Research, and by philanthropic gifts from Mr. and Mrs. Richard H. Deihl, Evelyn F. and Louis S. Grubb, Roscoe E. Hazard, Jr. and the Shultz Steel Company. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


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

JUPITER, FL - February 15, 2017 - Scientists are working to understand the mechanisms that make weight loss so complicated. Exercise burns calories, of course, but scientists are also looking at how the body burns more energy to stay warm in cold temperatures. Is there a way to get metabolism to ramp up--even when it's not cold out? TSRI Assistant Professor Anutosh Chakraborty is on a mission to answer this question. His past research revealed a new therapeutic target in this battle--a protein that actually promotes fat accumulation in animal models by slowing stored energy (fat) breakdown and encouraging weight gain. Now, in a study recently published online in the journal Molecular Metabolism, Chakraborty and his colleagues have shown that deleting the gene for this protein, known as IP6K1, protects animal models from both obesity and diabetes. This protective effect is seen regardless of diet, even at what's known as a thermoneutral temperature (around 86?F). This means inhibiting IP6K1 should help animals burn more energy, regardless of outside conditions. "In genetically altered animal models that lack IP6K1, we found that deletion dramatically protects these knock-out mice from diet-induced obesity and insulin resistance regardless of the temperature in the environment," Chakraborty said. "When we inhibited the enzyme with chemical compounds, the results were similar." Temperature is important in the study of obesity because an animal in lower temperatures will rapidly lose weight as it burns more energy to try to maintain core body temperature. Because humans can maintain their body temperatures in a number of ways--clothing, for example--any pathway that reduces body weight at higher temperatures is a highly encouraging target in human obesity. The new study suggests a future pharmaceutical may be able to target IP6K1 to mimic the energy burning seen at relatively lower temperatures. "If we delete IP6K1, the animals gain less body weight because they simply expend more energy--regardless of temperature. That's important because blocking weight gain by enhancing energy expenditure in a thermoneutral environment is harder and thus, targeting IP6K1 is expected to be successful in ameliorating obesity in humans," said Chakraborty. "If you're developing an anti-obesity drug based on inhibiting IP6K1, our new findings shows that there are potentially very few restrictions for its use--a subject would lose weight even on a high-fat diet, and nobody would have to sit in a refrigerator to make it work," he added. The first author of the study, "Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain," is TSRI's Qingzhang Zhu. Other authors are Sarbani Ghoshal, at TSRI at the time of the study, now at the Saint Louis University School of Medicine, and Richa Tyagi of the Johns Hopkins University School of Medicine. This work is supported by the National Institutes of Health (grant R01DK103746) and the state of Florida. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


News Article | January 27, 2016
Site: phys.org

To address that problem, scientists at the University at Buffalo and California Institute for Biomedical Research (Calibr) in La Jolla, California, are working to develop a therapy that could enable patients to control glucose levels while also losing weight. The treatment the researchers are developing is based on oxyntomodulin, a hormone that performs two important biological functions: First, it helps to keep glucose levels low by helping to increase insulin production. Second, the hormone encourages weight loss in part by facilitating processes that reduce food intake and increase the body's expenditure of energy. "On its own, oxyntomodulin has a short half-life. It's broken down quickly in the body, which means that patients would need to take it often and use high doses for it to work as a pharmaceutical," says Qing Lin, a chemistry professor in UB's College of Arts and Sciences. "We've modified the hormone's structure in a way that enhances its potency and enables it to survive in the body for longer periods of time, which allows for less frequent and more effective dosing." On Jan. 4 in ACS Chemical Biology, the researchers report that they have created several new versions of oxyntomodulin, including two that decreased blood glucose levels considerably in mice. Mice that received one of the two new compounds after ingesting glucose saw their glucose levels fall by 40 to 45 percent more than mice that received a placebo treatment. The two compounds also survived longer inside the animals than oxyntomodulin as it's found in nature. Lin was a senior author on the paper, along with Weijun Shen at Calibr. Lin has founded a startup, Transira Therapeutics, to further explore the potential therapy. In the body, oxyntomodulin regulates glucose levels and facilitates weight loss by binding to and activating two cellular receptors: the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). Oxyntomodulin performs its job best when it's in a certain helix conformation, but like many other peptide hormones, oxyntomodulin usually shifts between different shapes, including various helices and a random coil. Lin and his colleagues use a clever chemistry trick to help oxyntomodulin keep its helical shape. Their patented method is called chemical cross-linking. It involves engineering an oxyntomodulin molecule to include two groups of chemicals containing an amino acid called cysteine on different parts of the molecule, and then using a chemical linker to fasten those two groups together to make the molecule rigid. In cultured cells, cross-linked oxyntomodulin molecules were extremely effective in activating GCGR and GLP-1R, Lin and his colleagues reported in ACS Chemical Biology. The helical molecules are also harder for enzymes to break down, which helps the molecules survive longer in the body. Explore further: Surprise finding suggests diabetes drug could release rather than prevent blood sugar More information: Avinash Muppidi et al. Design of Potent and Proteolytically Stable Oxyntomodulin Analogs, ACS Chemical Biology (2016). DOI: 10.1021/acschembio.5b00787


February 21, 2017 - Results from a new Phase 3 study conducted by the Celgene Corporation demonstrate that ozanimod, a drug candidate originally discovered and optimized at The Scripps Research Institute (TSRI), can reduce the frequency of multiple sclerosis relapse. Relapsing multiple sclerosis is a form of the disease where patients experience a periodic worsening of symptoms. Sensory and motor loss of function leads to increased disability, and patients can need a cane or wheelchair. A signature of the disease is the appearance of lesions in the brain, which are linked to inflammation and can show up through MRI detection during active periods of multiple sclerosis relapse. Ozanimod, discovered by TSRI Professors Hugh Rosen and Ed Roberts and their laboratories, acts as a sphingosine 1-phosphate 1 (S1PR1) receptor agonist--modulating S1PR1 signaling and blocking sources of inflammation. Rosen and Roberts went on to co-found Receptos, a clinical stage biopharmaceutical company that took ozanimod into Phase 1, 2 and 3 clinical trials and was then acquired by Celgene. Ozanimod is the first New Chemical Entity discovered from a starting point in the NIH Common Fund Molecular Libraries Initiative to reach and succeed in advanced clinical studies. As reported by Celgene, results from the randomized, Phase 3, double-blind, double-dummy, active-controlled SUNBEAM study among 1,346 participants show that ozanimod met its primary endpoint in reducing annualized relapse rate (ARR) of relapsing multiple sclerosis, compared with an alternate drug treatment called weekly interferon (IFN) β-1a (Avonex®). Administered at doses of both 1 mg and 0.5 mg, ozanimod demonstrated statistically significant and clinically meaningful improvements, compared to Avonex®, for the primary endpoint of ARR and the measured secondary endpoints of the number of MRI-detected lesions and the number of new or enlarging "T2" MRI lesions at after a year of treatment. "It is exciting and rewarding to see the results of this new Phase 3 trial, which confirm the safety profile from the two-year extension data from the Phase 2 RADIANCE study and underscore ozanimod's efficacy in reducing the burden of MS symptoms on patients and their families," said Rosen. "We look forward to seeing the full study results, as well as the results from the Phase 3 study evaluating ozanimod in patients with ulcerative colitis." Scientists involved in the trial plan to present the full Phase 3 trial results at an upcoming international scientific meeting. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


Sun S.B.,Scripps Research Institute | Sen S.,Ohio State University | Kim N.-J.,Scripps Research Institute | Magliery T.J.,Ohio State University | And 2 more authors.
Journal of the American Chemical Society | Year: 2013

The monoclonal antibody 48G7 differs from its germline precursor by 10 somatic mutations, a number of which appear to be functionally silent. We analyzed the effects of individual somatic mutations and combinations thereof on both antibody binding affinity and thermal stability. Individual somatic mutations that enhance binding affinity to hapten decrease the stability of the germline antibody; combining these binding mutations produced a mutant with high affinity for hapten but exceptionally low stability. Adding back each of the remaining somatic mutations restored thermal stability. These results, in conjunction with recently published studies, suggest an expanded role for somatic hypermutation in which both binding affinity and stability are optimized during clonal selection. © 2013 American Chemical Society.


Kim C.H.,California Institute for Biomedical Research | Axup J.Y.,Scripps Research Institute | Schultz P.G.,California Institute for Biomedical Research | Schultz P.G.,Scripps Research Institute
Current Opinion in Chemical Biology | Year: 2013

The site-specific incorporation of unnatural amino acids with orthogonal chemical reactivity into proteins enables the synthesis of structurally defined protein conjugates. Amino acids containing ketone, azide, alkyne, alkene, and tetrazine side chains can be genetically encoded in response to nonsense and frameshift codons. These bio-orthogonal chemical handles allow precise control over the site and stoichiometry of conjugation, and have enabled medicinal chemistry-like optimization of the physical and biological properties of protein conjugates, especially the next-generation protein therapeutics. © 2013 .


Alvarez-Garcia O.,Scripps Research Institute | Rogers N.H.,California Institute for Biomedical Research | Smith R.G.,Scripps Research Institute | Lotz M.K.,Scripps Research Institute
Arthritis and Rheumatology | Year: 2014

Objective Obesity is a major risk factor for the development of osteoarthritis (OA) that is associated with a state of low-grade inflammation and increased circulating levels of adipokines and free fatty acids (FFAs). The aim of this study was to analyze the effects of saturated (palmitate) and monounsaturated (oleate) FFAs on articular chondrocytes, synoviocytes, and cartilage. Methods Human articular chondrocytes and fibroblast-like synoviocytes obtained from young healthy donors and OA chondrocytes from patients undergoing total knee replacement surgery were treated with palmitate or oleate alone or in combination with interleukin-1β (IL-1β). Cell viability, caspase activation, and gene expression of proinflammatory factors, extracellular matrix (ECM) proteins, and proteases were studied. In addition, chondrocyte viability, IL-6 production, and matrix damage were assessed in bovine and human articular cartilage explants cultured with FFAs in the presence or absence of IL-1β. Results Palmitate, but not oleate, induced caspase activation and cell death in IL-1β-stimulated normal chondrocytes, and up-regulated the expression of IL-6 and cyclooxygenase 2 in chondrocytes and fibroblast-like synoviocytes through Toll-like receptor 4 (TLR-4) signaling. In cartilage explants, palmitate induced chondrocyte death, IL-6 release, and ECM degradation. Palmitate synergized with IL-1β in stimulating proapoptotic and proinflammatory cellular responses. Pharmacologic inhibition of caspases or TLR-4 signaling reduced palmitate and IL-1β induced cartilage damage. Conclusion Palmitate acts as a proinflammatory and catabolic factor that, in synergy with IL-1β, induces chondrocyte apoptosis and articular cartilage breakdown. Collectively, our data suggest that elevated levels of saturated FFAs that are often found in patients who are obese may contribute to the pathogenesis of OA. Copyright © 2014 by the American College of Rheumatology.

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