The current application describes the research background, career development plan and Institutional commitment pertinent to the scientific career of the applicant. As required by the K02 mechanism, the applicant has already independent research support (R01 AI087803;NIAID).
The aim i s to strengthen and enhance the applicant's research efforts by providing at least 75% protected research time and thereby improving opportunities for building a successful science career. The applicant's studies are focusing on a novel domain of gastro-intestinal enzymology related to celiac disease. Celiac disease is an auto-immune disorder in which a host anti-self response is triggered by gluten-derived peptides in genetically predisposed individuals. Symptoms can be mostly reversed upon adherence to a gluten-free diet. Currently this avoidance strategy is the only treatment option available to celiac patients. It requires a life-long commitment to the gluten-free regimen and represents a social as well as a financial burden to the patient. One of the promising new therapeutic avenues pursued for celiac disease is gluten degradation and detoxification with enzyme preparations. We have discovered that the oral microbiome is a novel and rich source of gluten-degrading enzymes. In the past year we have isolated characterized and speciated the gluten enzyme-producing microorganisms. The elucidation of natural resident bacteria degrading gluten in the upper gastro-intestinal tract opens new therapeutic opportunities to neutralize the deleterious effects of these proteins. The major research goals for the next five years are to (1) Determine microbial enzyme activities under mock- gastro/duodenal conditions;(2) To characterize, clone and recombinantly express the most promising enzyme candidates;(3) To assess gliadin detoxification by selected microbes and purified enzyme preparations in vitro in a T-cell proliferation assay and in vivo in a mouse model for celiac disease. In addition, future studies are planned to investigate the striking structural similarities between gliadins and salivary proline-rich proteins (PRPs), and to investigate if PRPs possess gluten-like properties in terms of their capability to enhance/modulate immune responses in diet-responsive and refractory celiac disease.

Public Health Relevance

Gluten are proteins which are not tolerated by people who suffer from celiac disease. A promising therapeutic approach is the use of enzymes as dietary supplements to achieve gluten degradation and detoxification in vivo. The current application seeks to identify novel gluten-degrading enzymes expressed by resident microbes of the human upper gastrointestinal tract for their exploitation in the treatment of celiac disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02AI101067-02
Application #
8681349
Study Section
Transplantation Biology &Immunology-2 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2013-06-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02118
Heller, D; Helmerhorst, E J; Oppenheim, F G (2017) Saliva and Serum Protein Exchange at the Tooth Enamel Surface. J Dent Res 96:437-443
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Tian, Na; Faller, Lina; Leffler, Daniel A et al. (2017) Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients. Appl Environ Microbiol 83:
Wei, Guoxian; Tian, Na; Siezen, Roland et al. (2016) Identification of food-grade subtilisins as gluten-degrading enzymes to treat celiac disease. Am J Physiol Gastrointest Liver Physiol 311:G571-80
Heller, D; Helmerhorst, E J; Gower, A C et al. (2016) Microbial Diversity in the Early In Vivo-Formed Dental Biofilm. Appl Environ Microbiol 82:1881-8
Tian, Na; Leffler, Daniel A; Kelly, Ciaran P et al. (2015) Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease. Am J Physiol Gastrointest Liver Physiol 309:G910-7
Wei, Guoxian; Tian, Na; Valery, Adriana C et al. (2015) Identification of Pseudolysin (lasB) as an Aciduric Gluten-Degrading Enzyme with High Therapeutic Potential for Celiac Disease. Am J Gastroenterol 110:899-908
Tian, Na; Messana, Irene; Leffler, Daniel A et al. (2015) Salivary proline-rich proteins and gluten: Do structural similarities suggest a role in celiac disease? Proteomics Clin Appl 9:953-64
Helmerhorst, Eva J; Wei, Guoxian (2014) Experimental Strategy to Discover Microbes with Gluten-degrading Enzyme Activities. Proc SPIE Int Soc Opt Eng 9112:
Vukosavljevic, D; Hutter, J L; Helmerhorst, E J et al. (2014) Nanoscale adhesion forces between enamel pellicle proteins and hydroxyapatite. J Dent Res 93:514-9

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