Oral microbial enzymes for the treatment of celiac disease

描述（由申请人提供）：当前的应用程序描述了研究背景，职业发展计划和机构的承诺有关的科学生涯的申请人。根据K 02机制的要求，申请人已经拥有独立的研究支持（R 01 AI 087803; NIAID）。其目的是通过提供至少75%的受保护的研究时间来加强和提高申请人的研究工作，从而提高建立成功的科学事业的机会。申请人的研究集中在与乳糜泻相关的胃肠酶学的新领域。乳糜泻是一种自身免疫性疾病，其中在遗传易感个体中由麸质衍生肽触发宿主抗自身反应。症状可以在坚持无麸质饮食后大部分逆转。目前，这种避免策略是乳糜泻患者唯一可用的治疗选择。它需要终身致力于无麸质方案，并对患者造成社会和经济负担。乳糜泻的一个有前途的新的治疗途径是用酶制剂降解麸质和解毒。我们已经发现，口腔微生物组是谷蛋白降解酶的一种新的丰富来源。在过去的一年里，我们已经分离，特征和形态的面筋酶生产微生物。天然驻留细菌降解上胃肠道中麸质的阐明为中和这些蛋白质的有害影响开辟了新的治疗机会。未来五年的主要研究目标是：（1）在模拟胃/十二指肠条件下测定微生物酶活性;（2）表征、克隆和重组表达最有前途的酶候选物;（3）在体外T细胞增殖试验和体内腹腔疾病小鼠模型中评估所选微生物和纯化酶制剂对麦醇溶蛋白的解毒作用。此外，本发明还提供了一种方法， 未来的研究计划调查麦醇溶蛋白和 唾液富含脯氨酸的蛋白质（PRPs），并研究PRPs是否具有类似麸质的特性 就其在饮食反应性和难治性乳糜泻中增强/调节免疫应答的能力而言。 相关性：麸质是一种蛋白质，患有乳糜泻的人不能耐受。一种有前途的治疗方法是使用酶作为膳食补充剂，以实现体内面筋降解和解毒。本申请寻求鉴定由人上胃肠道的常驻微生物表达的新型谷蛋白降解酶，用于将其用于治疗乳糜泻。

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.