Oral microbial enzymes for the treatment of celiac disease

用于治疗乳糜泻的口腔微生物酶

• 批准号: 8509426
• 负责人: Eva Josephine Helmerhorst
• 金额: $ 10.19万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509426
• 关键词: Adherence; Amino Acids; Bacteria; Barley; Binding; Biological Assay; Biological Models; C-terminal; CD4 Positive T Lymphocytes; Celiac Disease; Cereals; Chromatography; Cleaved cell; Cloning; Data; Dental Plaque; Development Plans; Diet; Digestion; Drug Metabolic Detoxication; Employee Strikes; Enzymatic Biochemistry; Enzymes; Future; Gliadin; Glutamine; Gluten; Goals; Human; Immune System Diseases; Immune response; In Vitro; Individual; Interferon Type II; Intestines; Investigation; Life; Liquid substance; Measurement; Microbe; National Institute of Allergy and Infectious Disease; Oral; Pancreas; Patients; Pepsin A; Peptide Hydrolases; Peptides; Peripheral; Preparation; Probiotics; Production; Proline; Property; Proteins; Recombinants; Refractory; Regimen; Research; Research Support; Role; Rye cereal; Saliva; Salivary; Science; Source; Stomach; Symptoms; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Time; Tissues; Transglutaminases; Trypsin; Upper digestive tract structure; Wheat; career; career development; chymotrypsin; clinical application; dietary supplements; enzyme activity; immunogenic; improved; in vivo; interest; microbial; microorganism; milligram; mouse model; novel; novel therapeutics; oral microbiome; proline-rich proteins; research study; response; salivary proline-rich proteins; social

DESCRIPTION (provided by applicant): 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 is 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. 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.

描述（由申请人提供）：当前申请描述了与申请人的科学职业有关的研究背景，职业发展计划和机构承诺。根据K02机制的要求，申请人已经拥有独立的研究支持（R01 AI087803； NIAID）。目的是通过提供至少75％的保护时间，从而改善建立成功的科学职业的机会，从而加强和增强申请人的研究工作。申请人的研究重点是与乳糜泻有关的胃肠道酶学的新领域。腹腔疾病是一种自身免疫性疾病，其中在遗传性易感个体中，由麸质衍生的肽触发宿主抗自身反应。遵守无麸质饮食，症状大多可以逆转。目前，这种回避策略是腹腔患者可用的唯一治疗选择。它需要对无麸质方案做出终身承诺，并代表了患者的社会和经济负担。对于乳糜泻的新治疗途径之一是麸质降解和酶制剂的排毒。我们发现口服微生物组是一种新颖而丰富的麸质酶来源。在过去的一年中，我们孤立地表征并指定了麸质酶产生的微生物。上胃肠道中的天然居民降解麸质的天然驻留细菌为中和这些蛋白质的有害作用带来了新的治疗机会。未来五年的主要研究目标是（1）在模拟胃/十二指肠条件下确定微生物酶活性； （2）表征，克隆和重组表达最有希望的酶候选物； （3）在T细胞增殖测定法和腹腔疾病模型中的体内评估选定的微生物和纯化的酶制剂的麦醇溶蛋白排毒。此外， 计划未来的研究来调查麦醇麦芽胶蛋白与 唾液脯氨酸富蛋白（PRP），并研究PRP是否具有麸质特性 它们在饮食反应性和难治性乳糜泻中增强/调节免疫反应的能力的术语。 相关性：面筋是蛋白质，患有腹腔疾病的人无法忍受。一种有希望的治疗方法是将酶用作饮食补充剂来实现麸质降解和体内排毒。当前的应用旨在鉴定由人类上胃肠道的居民微生物表达的新型麸质酶，以在治疗腹腔疾病的治疗中剥削。