Chymotrypsin C in pancreatitis

描述(由申请人提供)：本申请是对美国国立卫生研究院NOT-OD-09-058号通知的回应，该通知题为“美国国立卫生研究院宣布恢复法资金可用于竞争性修订申请”。这项竞争性修订拨款建议为消化酶Chymotrypsin C寻找新的多肽抑制剂。家长补助金研究Chymotrypsin C如何调节其他消化酶的激活和降解，以及Chymotrypsin C突变如何增加人类慢性胰腺炎的风险。一种高度特异的胰凝乳酶C抑制剂的可用将有助于实现母公司拨款中概述的特定目标，并提高研究计划的整体速度。我们建议使用噬菌体展示技术来选择候选的抑制剂；使用合成的和天然的糜蛋白酶C底物来表征这些抑制剂，并通过将抑制剂与糜蛋白酶C共结晶来确定特异性抑制的结构基础。 与公共卫生相关：目前的赠款提案旨在开发针对人类胰凝乳蛋白酶C的新型抑制剂，这是一种消化酶，在调节其他消化酶方面发挥重要作用，并与慢性胰腺炎的发展有关，慢性胰腺炎是一种经常使人虚弱的疾病。这一结果可以促进人类胰腺炎新的诊断和治疗干预措施的发展。

DESCRIPTION (provided by applicant): This application is in response to NIH notice NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". This competitive revision grant proposes to identify novel peptide inhibitors for the digestive enzyme chymotrypsin C. The parent grant investigates how chymotrypsin C regulates activation and degradation of other digestive enzymes and how mutations in chymotrypsin C increase the risk of chronic pancreatitis in humans. The availability of a highly specific chymotrypsin C inhibitor would facilitate the accomplishment of the specific aims outlined in the parent grant and enhance the overall tempo of the research program. We propose to use phage display technology to select candidate inhibitors; to characterize these inhibitors using both synthetic and natural chymotrypsin C substrates and to determine the structural basis of specific inhibition by co-crystallizing inhibitors with chymotrypsin C. PUBLIC HEALTH RELEVANCE: The present grant proposal intends to develop novel inhibitors against human chymotrypsin C, a digestive enzyme, which plays an important role in regulating other digestive enzymes and has been linked to the development of chronic pancreatitis, an often debilitating disease. The results can advance the development of novel diagnostic and therapeutic interventions for human pancreatitis.