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Tor Savidge Lab

Tor Savidge Lab Research

Master
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Neuroimmune-Microbial Interactions Laboratory

Dr. Savidge is interested in studying neuroimmune-microbial interactions in the gastrointestinal tract using a range of techniques that include computational and structural biology, global metabolomics and proteomics, realtime molecular interactions, cell culture and humanized disease models. These studies have found that gut astrocytes are important regulators of mucosal barrier function and inflammation in inflammatory bowel disease, necrotizing enterocolitis and Clostridium difficile infection. A novel innate host defense mechanism for subverting microbial pathogenesis has also been identified and is being translated into a prototypic form of therapy termed allosteric therapeutics. In clinical trials, the efficacy of this approach remains highly uncertain since patients with severe CDI typically tend to be the elderly and the critically ill. Systemic antitoxin immunotherapy.

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R01 NIAID AI10094001 (May 2012 - May 2017)

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Allosteric therapy of the Clostridium difficile toxins

The goal of this study is to develop novel allosteric inhibitors for the C. difficile toxins using inositolphosphate analogs and S-nitrosothiol biology.

Clostridium difficile infection (CDI) is one of the most prolific causes of bacterial-induced diarrhea in the United States, with 3 million cases estimated annually. Newly emerged in its hypervirulent form, C. difficile also causes serious and potentially fatal inflammation of the colon. Because C. difficile is rapidly developing resistance to antibiotic treatment, there is an urgent need to find an alternative therapy. Vancomycin and metronidazole remain treatment options for CDI, but neither is fully effective as is evident by the unacceptably high relapse rates. Two large enterotoxins (TcdA and TcdB) are the known causes of C. difficile-associated disease. Although an antitoxin vaccine program is currently has recently been reported to be effective in preventing disease relapse in CDI patients, but fails to confer significant clinical benefits or reduce the length of hospitalization. Oral adaptation of passive antitoxin immunotherapy is currently not feasible or economical. Thus, there is an urgent need to develop new oral therapeutics for CDI. Our goal is to address these critical issues by performing highly innovative studies of the toxin virulence mechanism and by developing prototypic concepts for oral allosteric therapeutics that neutralize toxin activity in the colon. This work will be performed as a multi-institutional collaborative effort involving basic and clinical expertise of the C. difficile toxins, and in generating novel antitoxin therapeutics.

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NIH 1UL1RR029876-01 (September 2010 - August 2013)

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Development of Novel Therapeutics for Clostridium difficile infection

The goal of this project is to establish a Multidisciplinary Translational Team (MTT) of investigators and clinicians to work on developing novel therapeutics and diagnostics for C. difficile infection.

Global Metabolomics

Identification and quantification of these small molecules in patient stool specimens has been facilitated by a proprietary global metabolomics platform developed by Metabolon LLC, who has been an active collaborative partner in this research effort.

Dr. Savidge's aims to continue his focus on the application of this unique metabolomics platform to identify stool biomarkers in children with functional bowel disorders that correlate with mindfulness meditation therapy. As associate director of the Texas Children’s Microbiome Center and full member of the NIDDK-funded Texas Medical Center Digestive Diseases Center, he is collaborating with other investigators in this field to establish metabolomics and visual bioinformatics using a range of techniques that include computational and structural biology, global metabolomics and proteomics, realtime molecular interactions, cell culture and humanized disease models to systematically investigate functional patient-microbial-metabolite interactions.

Gut Astrocytes

These studies have found that gut astrocytes are important regulators of mucosal barrier function and inflammation in inflammatory bowel disease, necrotizing enterocolitis and Clostridium difficile infection. A novel innate host defense mechanism for subverting microbial pathogenesis has also been identified and is being translated into a prototypic form of therapy termed allosteric therapeutics.