Oral microbial enzymes for the treatment of celiac disease

描述（由申请人提供）：当前申请表描述了与申请人科学生涯相关的研究背景，职业发展计划和机构承诺。根据K02机制要求，申请人已获得独立研究支持（R01 AI087803； NIAID）。其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道酶学新领域。乳糜泻是一种自身免疫性疾病，在遗传易感个体中，由谷蛋白衍生肽引发宿主抗自我反应。坚持无麸质饮食后，症状大多可以逆转。目前，这种避免策略是乳糜泻患者唯一可用的治疗选择。它需要终生坚持无麸质饮食，对患者来说不仅是一种社会负担，也是一种经济负担。一个有希望的新的治疗途径追求乳糜泻是谷蛋白降解和解毒的酶制剂。我们已经发现口腔微生物群是一种新的丰富的谷蛋白降解酶来源。在过去的一年里，我们已经分离出了面筋酶产生微生物的特征和物种。降解上消化道谷蛋白的天然常驻细菌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)对最有前途的候选酶进行鉴定、克隆和重组表达；(3)在体外t细胞增殖试验和腹腔疾病小鼠模型中评估选定微生物和纯化酶制剂对麦胶蛋白的解毒作用。此外,

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.