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Measurement of protease activity in vivo

体内蛋白酶活性的测量

基本信息

批准号：
8427291
负责人：
Patrick S Daugherty
金额：
$ 34.59万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8427291
关键词：
Active Sites Address Affinity Animals Antibodies Antibody Binding Sites Apolipoprotein E Atherosclerosis Binding Biological Process Blocking Antibodies Cardiovascular Diseases Characteristics Communicable Diseases Data Detection Development Diagnostic Diagnostic Imaging Disease Engineering Enzymes Event Exhibits Family Fluorescence Resonance Energy Transfer Generic Drugs Half-Life Health Homologous Gene Hour Human Image Immunofluorescence Immunologic Immunoglobulin G In Vitro Individual Inflammatory Life Ligands MMP14 gene Magnetic Resonance Imaging Malignant Neoplasms Masks Measurement Measures Mediating Methods Molecular Probes Mus Organism Pathogenesis Pathologic Pathologic Processes Peptide Hydrolases Peptide Library Peptide antibodies Peptides Performance Physiological Physiological Processes Play Positron-Emission Tomography Process Regulation Reporting Role Site Specificity Thrombin Tissues Translating Whole Organism Yeasts base design directed evolution flexibility fluorescence imaging in vivo mouse model novel novel strategies novel therapeutic intervention polymerization scaffold tool uptake

项目摘要

DESCRIPTION (provided by applicant): Protease activities are known to be critical in the pathogenesis of a wide variety of diseases including cancer, cardiovascular disease, and inflammatory and infectious diseases. Although large-scale efforts are providing valuable information regarding the expression of many diverse proteases in normal and disease tissues, these methods do not report the functional activity of proteases. Protease beacons are emerging as a powerful tool to non-invasively measure protease activity in vivo, and will benefit from approaches that enable more selective cleavage by individual targeted proteases and probe retention at the site of activation. This project aims to validate a generic molecular probe design to detect, localize, and quantify protease activities in vivo in normal and pathologic tissues and whole organisms. Specifically, a new class of protease activity probes will be created that exhibit the desired characteristics of high tissue uptake, selective activation by individual target proteases, and accumulation at sites of activation. The utility of these probes for the localization and quantification of protease activities in vivo will be demonstrated in normal mice and the ApoE(-/-) mouse model of atherosclerosis. Completion of this project will yield probes that accurately and reliably report the activity of proteases involved in normal and pathologic processes, with high potential for translational to humans. More generally, successful completion of the aims of this proposal will open the door to the measurement and localization of a wide range of protease activities in living organisms with high spatial and temporal precision.

描述（由申请人提供）：已知蛋白酶活性在包括癌症、心血管疾病以及炎性和感染性疾病在内的多种疾病的发病机理中是关键的。尽管大规模的努力提供了关于许多不同蛋白酶在正常和疾病组织中的表达的有价值的信息，但这些方法没有报道蛋白酶的功能活性。蛋白酶信标正在成为一种强有力的工具，非侵入性地测量体内蛋白酶活性，并将受益于方法，使更多的选择性切割个别靶向蛋白酶和探针保留在激活位点。该项目旨在验证一种通用的分子探针设计，以检测，定位和定量蛋白酶活性在体内正常和病理组织和整个生物体。具体而言，将产生一类新的蛋白酶活性探针，其表现出高组织摄取、通过单个靶蛋白酶的选择性活化和在活化位点的积累的期望特征。将在正常小鼠和动脉粥样硬化的ApoE（-/-）小鼠模型中证明这些探针用于体内蛋白酶活性的定位和定量的效用。该项目的完成将产生准确可靠地报告参与正常和病理过程的蛋白酶活性的探针，具有很高的翻译人类的潜力。更一般地说，成功完成本提案的目标将打开大门，以高的空间和时间精度的测量和定位的范围广泛的蛋白酶活性的活生物体。