Oral microbial enzymes for the treatment of celiac disease

描述(由申请人提供)：目前的申请描述了与申请人的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机制的要求，申请人已经拥有独立的研究支持(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加强申请者的研究努力，从而改善建立成功的科学事业的机会。申请者的研究集中在与乳糜泻相关的胃肠道酶学的一个新领域。乳糜泻是一种自身免疫性疾病，在这种疾病中，宿主的抗自我反应是由遗传易感个体中的面筋衍生多肽触发的。只要坚持无麸质饮食，症状基本上可以逆转。目前，这种回避策略是乳糜泻患者唯一可用的治疗选择。这需要终身致力于无麸质养生法，对患者来说既是一种社会负担，也是一种经济负担。面筋降解和酶制剂解毒是治疗乳糜泻的一条很有前途的新途径。我们发现，口腔微生物群是面筋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、鉴定和鉴定了面筋酶产生菌。上胃肠道中天然驻留的面筋降解细菌的阐明为中和这些蛋白质的有害影响打开了新的治疗机会。未来五年的主要研究目标是：(1)测定模拟胃/十二指肠条件下的微生物酶活性；(2)鉴定、克隆并重组表达最有前景的候选酶；(3)通过T细胞增殖实验和小鼠乳糜泻模型，评估选定的微生物和纯化的酶制剂对醇溶蛋白的解毒作用。此外, 未来的研究计划调查醇溶蛋白和醇溶蛋白之间惊人的结构相似性 唾液中富含脯氨酸的蛋白(PRPS)，并研究PRPS是否具有面筋样特性 在饮食敏感型和难治性乳糜泻中增强/调节免疫反应的能力。 相关性：面筋是乳糜泻患者所不能忍受的蛋白质。一种有前景的治疗方法是使用酶作为饮食补充剂，在体内实现面筋降解和解毒。目前的应用旨在鉴定人类上消化道驻留微生物表达的新的面筋降解酶，以便在乳糜泻的治疗中开发它们。

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.