Celiac sprue is an immune disease of the small intestine that is triggered by dietary gluten. A fundamental molecular understanding of celiac sprue pathogenesis is essential for the development of improved diagnosis and disease management strategies. Over the past few years, we have contributed to this endeavor in the following ways: (i) We established an intimate link between the immunotoxicity of gluten and its proteolytic resistance in the GI tract;(ii) We translated this insight into the design and development of promising oral enzyme therapies (""""""""glutenases"""""""");(iii) We developed chemical reagents, X-ray crystallographic insights and biochemical assay systems to probe transglutaminase 2 (TG2), whose relevance to celiac pathogenesis is generally acknowledged but inadequately understood;(iv) We harnessed these molecular tools to show that TG2 is ordinarily inactive in the small intestine, but is transiently activated by innate inflammatory signals;(v) We solved the X-ray crystal structure of DQ2, and investigated the kinetics and thermodynamics of gluten peptide interaction with this disease associated HLA;and (vi) We exploited these structural and biochemical insights to identify gluten peptide analogues that block DQ2- mediated gluten antigen presentation to patient-derived inflammatory T cells.
Our Specific Aims during the next proposal period are to: (i) Develop biomarkers to monitor in vivo glutenase efficacy in pilot proof-of-concept human clinical trials;(ii) Understand the mechanism and consequences of transient TG2 activation in the celiac small intestine;and (iii) Develop improved blockers of DQ2 mediated antigen presentation, and improved assays to quantify the efficacy of these blockers. Together, these studies will enhance our knowledge of gluten-induced pathogenesis in celiac sprue, and could also lead to new opportunities for celiac diagnosis and/or therapy.

Public Health Relevance

Celiac sprue is a gluten-induced autoimmune disease for which no therapies are currently available other than an expensive and highly restrictive diet. During the past funding period, we have investigated selected aspects of the molecular pathogenesis of this disease, and have started to translate these insights into practical tools for disease management. During the next proposal period we propose to continue such studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063158-08
Application #
7880738
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2002-10-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
8
Fiscal Year
2010
Total Cost
$323,843
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Yi, Michael C; Melkonian, Arek V; Ousey, James A et al. (2018) Endoplasmic reticulum-resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2. J Biol Chem 293:2640-2649
Plugis, Nicholas M; Weng, Nielson; Zhao, Qinglan et al. (2018) Interleukin 4 is inactivated via selective disulfide-bond reduction by extracellular thioredoxin. Proc Natl Acad Sci U S A 115:8781-8786
Palanski, Brad A; Khosla, Chaitan (2018) Cystamine and Disulfiram Inhibit Human Transglutaminase 2 via an Oxidative Mechanism. Biochemistry 57:3359-3363
Syage, Jack A; Murray, Joseph A; Green, Peter H R et al. (2017) Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet. Dig Dis Sci 62:2428-2432
Guo, Shunling; Palanski, Brad A; Kloeck, Cornelius et al. (2017) Intracellular TG2 Activity Increases Microtubule Stability but is not Sufficient to Prompt Neurite Growth. Neurosci Bull 33:103-106
Plugis, Nicholas M; Palanski, Brad A; Weng, Chih-Hisang et al. (2017) Thioredoxin-1 Selectively Activates Transglutaminase 2 in the Extracellular Matrix of the Small Intestine: IMPLICATIONS FOR CELIAC DISEASE. J Biol Chem 292:2000-2008
Bouziat, Romain; Hinterleitner, Reinhard; Brown, Judy J et al. (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356:44-50
Hilmer, Andrew J; Jeffrey, R Brooke; Park, Walter G et al. (2017) Cholestyramine as a promising, strong anion exchange resin for direct capture of genetic biomarkers from raw pancreatic fluids. Biotechnol Bioeng 114:934-938
Khosla, Chaitan (2017) Celiac Disease: Lessons for and from Chemical Biology. ACS Chem Biol 12:1455-1459
Wibowo, Arif; Park, Jae Mo; Liu, Shie-Chau et al. (2017) Real-Time in Vivo Detection of H2O2 Using Hyperpolarized 13C-Thiourea. ACS Chem Biol 12:1737-1742

Showing the most recent 10 out of 74 publications