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    Protein Engineering May Fuel Breakthroughs in Celiac and Other Diseases 


    Jefferson Adams
    • Recent breakthroughs are helping researchers to decipher the rules that predict how proteins fold into those three-dimensional structures are fueling research in brain protein science, and offering tremendous hope for celiac and other diseases.

    Protein Engineering May Fuel Breakthroughs in Celiac and Other Diseases 
    Image Caption: Image: CC--Oak Ridge National Laboratory

    Celiac.com 05/22/2018 - Proteins are the building blocks of life. If scientists can figure out how to create and grow new proteins, they can create new treatments and cures to a multitude of medical, biological and even environmental conditions.

    For a couple of decades now, scientists have been searching for a biological Rosetta stone that would allow them to engineer proteins with precision, but the problem has remained dauntingly complex.  Researchers had a pretty good understanding of the very simple way that the linear chemical code carried by strands of DNA translates into strings of amino acids in proteins. 

    But, one of the main problems in protein engineering has to do with the way proteins fold into their various three-dimensional structures. Until recently, no one has been able to decipher the rules that will predict how proteins fold into those three-dimensional structures.  So even if researchers were somehow able to design a protein with the right shape for a given job, they wouldn’t know how to go about making it from protein’s building blocks, the amino acids.

    But now, scientists like William DeGrado, a chemist at the University of California, San Francisco, and David Baker, director for the Institute for Protein Design at the University of Washington, say that designing proteins will become at least as important as manipulating DNA has been in the past couple of decades.

    After making slow, but incremental progress over the years, scientists have improved their ability to decipher the complex language of protein shapes. Among other things, they’ve gained a better understanding of how then the laws of physics cause the proteins to snap into folded origami-like structures based on the ways amino acids are attracted or repelled by others many places down the chain.

    It is this new ability to decipher the complex language of protein shapes that has fueled their progress. UCSF’s DeGrado is using these new breakthroughs to search for new medicines that will be more stable, both on the shelf and in the body. He is also looking for new ways to treat Alzheimer’s disease and similar neurological conditions, which result when brain proteins fold incorrectly and create toxic deposits.

    Meanwhile, Baker’s is working on a single vaccine that would protect against all strains of the influenza virus, along with a method for breaking down the gluten proteins in wheat, which could help to generate new treatments for people with celiac disease. 

    With new computing power, look for progress on the understanding, design, and construction of brain proteins. As understanding, design and construction improve, look for brain proteins to play a major role in disease research and treatment. This is all great news for people looking to improve our understanding and treatment of celiac disease.

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, and science. He previously served as Health News Examiner for Examiner.com, and provided health and medical content for Sharecare.com.

    Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book Dangerous Grains by James Braly, MD and Ron Hoggan, MA.

  • Related Articles

    Scott Adams
    Celiac.com 05/14/2000 - Scientists from the University of Maryland have discovered that people with the autoimmune disorder celiac disease have higher levels of the protein zonulin in their bodies. This discovery may ultimately lead to more insight into the causes of other autoimmune diseases, including diabetes, multiple sclerosis and rheumatoid arthritis. In people with celiac disease who eat gluten, which is found in wheat, rye and barley, an autoimmune reaction is set off that creates antibodies that end up attacking their intestines. This causes symptoms like diarrhea and abdominal pain, and may lead to long-term damage and a large host of other problems. Researchers at the University of Maryland have finally found the cause of this curious reaction: a protein in the body called zonulin.
    Zonulin is a human protein that acts like a traffic conductor for the bodys tissues by opening spaces between cells, and allowing certain proteins to pass through, while keeping out toxins and bacteria. People with celiac disease have higher levels of zonulin, which apparently allows gluten to pass through the cells in their intestines, which triggers an autoimmune response in their bodies. Until now, researchers could never understand how a big protein like gluten could pass through the immune system. According to author Alessio Fasano, M.D., people with celiac have an increased level of zonulin, which opens the junctions between the cells. In essence, the gateways are stuck open, allowing gluten and other allergens to pass. Further: I believe that zonulin plays a critical role in the modulation of our immune system...(f)or some reason, the zonulin levels go out of whack, and that leads to autoimmune disease. Ultimately these finding may help doctors understand the causes of other, more severe autoimmune disorders.

    Jefferson Adams
    Brain Abnormalities in Patients with Celiac Disease and Neurological Issues
    Celiac.com 09/17/2012 - Many aspects of celiac disease simply have not been well studied, so they remain poorly understood. For example, researchers have not done enough study on people with celiac disease to understand if they show any readily available serological markers of neurological disease.
    To better understand this issue, a research team recently assessed the amount of brain abnormality in patients with celiac disease, along with looking into MR imaging sequences as biomarkers for neurological dysfunction.
    The study team included S. Currie, M. Hadjivassiliou, M.J. Clark, D.S. Sanders, I.D. Wilkinson, P.D. Griffiths, and N. Hoggard, of the Academic Unit of Radiology at University of Sheffield, Royal Hallamshire Hospital, in Sheffield, UK.
    For their study, they conducted a retrospective examination of a consecutive group of 33 patients with biopsy proven celiac disease, who had been referred for neurological opinion. The group ranged in age from 19 to 64 years old, with an average of 44±13 years.
    Researchers divided the group into subgroups based on their main neurological complaints of balance disturbance, headache and sensory loss.
    They used 3T MR to evaluate variations in brain grey matter density, cerebellar volume, cerebellar neurochemistry and white matter abnormalities (WMAs) between celiac patients and control subjects.
    The results showed that the celiac patients had a significantly lower cerebellar volume than did control subjects. Celiac patients had 6.9±0.7% of total intracranial volume, compared with 7.4±0.9% for control subjects (p<0.05).
    Celiac patients also showed significantly less grey matter density in multiple brain regions, both above and below the tentorium cerebelli, compared with the control subjects (p<0.05).
    The data showed that 12 (36%) patients demonstrated WMAs unexpected for the patient's age, with the highest incidence occurring in the headache subgroup.
    This group of patients averaged nearly double the number of WMAs per MR imaging session than the subgroup with balance disturbance, and six times more than the subgroup with sensory loss.
    The MR images of celiac patients who have neurological symptoms show significant brain abnormality on MR imaging, which means that MR imaging may serve as valuable biomarkers of disease in celiac patients.
    Source:
    J Neurol Neurosurg Psychiatry. 2012 Aug 20.

    Jefferson Adams
    Celiac.com 12/29/2014 - While the immune response to gluten proteins in celiac disease has been well researched, and is pretty well understood, researchers really don’t know much about the immune response to non-gluten proteins in wheat. A team of researchers recently set out to determine the level and molecular specificity of antibody response to wheat non-gluten proteins in celiac disease.
    The research team included Sina Huebener, Charlene K. Tanaka, Melanie Uhde, John J. Zone, William H. Vensel, Donald D. Kasarda §, Leilani Beams, Chiara Briani, Peter H. R. Green, Susan B. Altenbach, and Armin Alaedini. They are variously affiliated with the Department of Medicine at Columbia University in New York, New York, USA, the Celiac Disease Center at Columbia University in New York, New York, USA, the Western Regional Research Center, Agricultural Research Service of the United States Department of Agriculture in Albany, California, USA, the Department of Dermatology at the University of Utah in Salt Lake City, Utah, USA, the Department of Neurosciences at the University of Padova, in Padova, Italy, and the Institute of Human Nutrition at Columbia University in New York, New York, USA.
    Together, the team screened blood samples from celiac patients and control subjects for IgG and IgA antibody reactivity to a non-gluten protein extract taken from the wheat cultivar Triticum aestivum Butte 86.
    They also analyzed the antibodies for reactivity to specific non-gluten proteins by two-dimensional gel electrophoresis and immunoblotting. They used tandem mass spectrometry to identify any immuno-reactive molecules.
    They found that, compared with healthy control subjects, celiac patients showed significantly higher levels of antibody reactivity to non-gluten proteins. The main immuno-reactive non-gluten antibody culprit proteins were serpins, purinins, α-amylase/protease inhibitors, globulins, and farinins.
    Assessment of reactivity toward purified recombinant proteins further confirmed the presence of antibody response to specific antigens.
    These results show that, in addition to the well-understood immune reaction to gluten, people with celiac disease experience reactions to a number of non-gluten proteins of wheat.
    The short take away is that the bodies of people with celiac disease show clear immune responses, not just to gluten proteins in wheat, but to non-gluten proteins, as well.
    Source:
    J. Proteome Res., DOI: 10.1021/pr500809b

    Jefferson Adams
    Celiac.com 05/16/2016 - A number of epidemiological and clinical studies suggest a connection between inflammation and Alzheimer disease, their relationship is not well understood and may have implications for treatment and prevention strategies.
    A research team recently set out to figure out if a subset of genes involved with increased risk of inflammation are also associated with increased risk for Alzheimer disease. The research team included JS Yokoyama, Y Wang, AJ Schork, WK Thompson, CM Karch, C Cruchaga, LK McEvoy, A Witoelar, CH Chen, D Holland, JB Brewer, A Franke, WP Dillon, DM Wilson, P Mukherjee, CP Hess, Z Miller, LW Bonham, J Shen, GD Rabinovici, HJ Rosen, BL Miller, BT Hyman, GD Schellenberg, TH Karlsen, OA Andreassen, AM Dale, RS Desikan; and the Alzheimer’s Disease Neuroimaging Initiative.
    They are variously affiliated with the Departments of Neurosciences, Cognitive Sciences, Psychiatry, and Radiology at the University of California, San Diego, La Jolla, the Departments of Neurology, Radiology and Biomedical Imaging at the University of California, San Francisco, the Department of Psychiatry, Washington University, St Louis, Missouri, the Division of Mental Health and Addiction, Oslo University Hospital, the Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, the Division of Gastroenterology, and the Norwegian PSC Research Center and KG Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation at Oslo University Hospital Rikshospitalet, Oslo, Norway, the Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany, the Department of Neurology, Massachusetts General Hospital, Boston, and the Department of Pathology and Laboratory Medicine at the University of Pennsylvania Perelman School of Medicine, Philadelphia.
    Using data from numerous genome-wide association studies from several clinical research centers, the team conducted a genetic epidemiology study in July 2015, in which they systematically investigated genetic overlap between Alzheimer disease (International Genomics of Alzheimer's Project stage 1) and Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis.
    The team assessed P values and odds ratios from genome-wide association studies of more than 100, 000 individuals from previous comparisons of patients vs respective control groups. They used consensus criteria to confirm diagnosis for each disorder previously made in the parent study. The main outcome was the pleiotropic (conjunction) false discovery rate P value.
    Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer's Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer's Disease Neuroimaging Initiative); and gene expression in Alzheimer disease vs control brains (Gene Expression Omnibus data).
    These findings confirm genetic overlap between Alzheimer disease and immune-mediated diseases, and suggest that immune system processes influence Alzheimer disease pathogenesis and progression.
    For more detail, and exact data results, see JAMA Neurol. 2016 Apr 18. doi: 10.1001/jamaneurol.2016.0150.

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