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: 9067914
• 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/9067914
• 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; Genetic Predisposition to Disease; 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; western diet

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相关的研究背景、职业发展计划和机构承诺。根据K02机制的要求，申请人已获得独立研究支持（R01 AI087803；NIAID）。目的是通过提供至少 75% 受保护的研究时间来加强和提高申请人的研究工作，从而增加建立成功的科学事业的机会。申请人的研究重点是与乳糜泻相关的胃肠酶学新领域。乳糜泻是一种自身免疫性疾病，在遗传易感人群中，宿主的抗自身反应是由麸质衍生肽引发的。坚持无麸质饮食后，症状大部分可以逆转。目前，这种避免策略是乳糜泻患者唯一可用的治疗选择。它需要终生致力于无麸质疗法，并且给患者带来社会和经济负担。乳糜泻的有希望的新治疗途径之一是用酶制剂进行麸质降解和解毒。我们发现口腔微生物组是麸质降解酶的新型且丰富的来源。在过去的一年里，我们对产生麸质酶的微生物进行了分离和鉴定。上胃肠道中天然驻留细菌降解麸质的阐明为中和这些蛋白质的有害作用开辟了新的治疗机会。未来五年的主要研究目标是（1）确定模拟胃/十二指肠条件下的微生物酶活性； (2) 表征、克隆和重组表达最有希望的候选酶； (3) 在体外 T 细胞增殖测定中和体内乳糜泻小鼠模型中评估选定微生物和纯化酶制剂的麦醇溶蛋白解毒作用。此外， 未来的研究计划调查麦醇溶蛋白和麦醇溶蛋白之间惊人的结构相似性 唾液富含脯氨酸的蛋白质（PRP），并研究 PRP 是否具有麸质样特性 就其增强/调节饮食反应性和难治性乳糜泻免疫反应的能力而言。 相关性：麸质是乳糜泻患者无法耐受的蛋白质。一种有前景的治疗方法是使用酶作为膳食补充剂来实现体内麸质降解和解毒。目前的申请旨在鉴定由人类上胃肠道常驻微生物表达的新型麸质降解酶，用于治疗乳糜泻。