De-orphanizing MMPs in intercelluar interactions

细胞间相互作用中 MMP 的去孤儿化

• 批准号: 9176901
• 负责人: Jeffrey W Smith
• 金额: $ 52.24万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176901
• 关键词: Alzheimer' s Disease; Animals; Arterial Fatty Streak; Arthritis; Biological; Biological Process; Biology; Catalytic Domain; Cell model; Cell physiology; Cells; Cleaved cell; Communities; Conflict (Psychology); Data Set; Deposition; Disease; Drug Delivery Systems; Event; Family; Foundations; Funding; Goals; Hemopexin; Histocompatibility Testing; Human; Image; Individual; Infection; Inflammation; Institutes; Knowledge; Length; Link; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Medical; Orphan; Outcome Study; Paper; Pathology; Pathway interactions; Peptide Hydrolases; Peptides; Phage Display; Positioning Attribute; Probability; Process; Proteolysis; Proteome; Proteomics; Publications; Publishing; Pulmonary Emphysema; Research; Role; Specificity; Stromelysin 1; Structure; Structure-Activity Relationship; Substrate Specificity; System; Testing; The Cancer Genome Atlas; Thrombosis; United States National Institutes of Health; Work; base; cell type; chemokine; computerized tools; genome wide association study; human disease; member; new therapeutic target; research study; web site

PROJECT SUMMARY Proteolytic pathways are involved in virtually every human disease including, cancer, thrombosis, arthritis, infection, inflammation, and Alzheimer's disease. Many of these cleavage events take place at the interface between cells, and they regulate intracellular interactions, especially those driven by the matrix metalloproteinases (MMPs). More than 40,000 papers have been published on these proteases, and “MMP” is topic of more than 400 currently funded NIH grants. This massive body of work contains important information, but at this point any single publication on MMPs advances our knowledge only incrementally. In fact, for the “popular” MMPs, much of the information being collected is conflicting, raising more questions than answers. On the other hand though, substrates have not even been identified for nearly one-half of the MMP family. The long-term objective of this project is to shift the paradigm in MMP research by making a major advance in our understanding of the structure-function relationships that guide substrate selectivity of the MMPs. To accomplish this objective we will study MMP structure and function at the systems level. Rather than trying to understand how one MMP cleaves a substrate, we will quantitatively describe how every protease in the family recognizes and cleaves its substrates. The Specific Aims of the project are to test the following hypotheses: 1) that each specificity determining position within the MMP catalytic domain makes a different contribution to substrate selectivity, 2) that physiologic (and pathophysiologic) substrates of the MMPs can be predicted by placing knowledge on subsite specificity at the catalytic cleft into physiologic context, 3) that the MMP hemopexin (HPX) domain modulates but does not alter substrate recognition and selectivity. The outcome of the study will provide the essential foundation for understanding MMP function in biology and pathology at the systems level. The study will reveal the structural basis for specialization and expansion of function, which remains one of the most important unanswered questions in biology. The work will also reveal a host of new therapeutic targets because the substrates are the real downstream effectors of MMP activity. Additionally, the study will generate peptide substrates that are highly selective for individual matrix metalloproteinases. These substrates can be used to devise agents to image proteolysis in animals and in humans. The same substrates could also be employed to create targeted drug delivery vehicles. Finally, all information derived from the study, computational tools, results, predictions, proteomic analysis and interpretations will be deposited on our Proteolysis MAP website (www.proteolysis.org) for use by the scientific and medical community.

项目概要 蛋白水解途径几乎涉及所有人类疾病，包括癌症、血栓形成、 关节炎、感染、炎症和阿尔茨海默病。许多这些裂解事件发生在 细胞之间的界面，它们调节细胞内的相互作用，特别是那些由基质驱动的相互作用 金属蛋白酶（MMP）。有关这些蛋白酶的论文已发表超过 40,000 篇，其中“MMP”是 目前 NIH 资助的 400 多项资助的主题。这部庞大的著作包含了重要的信息， 但目前任何关于 MMP 的出版物都只能渐进地增进我们的知识。事实上，对于 “流行的”MMP，收集到的许多信息都是相互矛盾的，提出的问题多于答案。 但另一方面，近一半的 MMP 家族的底物尚未确定。 该项目的长期目标是通过重大研究来改变 MMP 研究范式 进一步加深了我们对指导 MMP 底物选择性的结构-功能关系的理解。 为了实现这一目标，我们将研究系统级别的 MMP 结构和功能。而不是尝试 为了了解一种 MMP 如何切割底物，我们将定量描述该家族中的每种蛋白酶如何 识别并裂解其底物。 该项目的具体目标是测试以下假设：1）每个特异性决定 MMP 催化结构域内的位置对底物选择性有不同的贡献，2) MMP 的生理（和病理生理）底物可以通过将知识放在子位点上来预测 催化裂隙进入生理环境的特异性，3) MMP 血红素 (HPX) 结构域可调节，但 不改变底物识别和选择性。 该研究结果将为理解MMP在生物学中的功能提供必要的基础 和系统层面的病理学。该研究将揭示专业化和扩展的结构基础 功能，这仍然是生物学中最重要的未解答问题之一。该作品还将揭示 由于底物是 MMP 活性的真正下游效应子，因此成为许多新的治疗靶点。 此外，该研究将产生对单个基质具有高度选择性的肽底物 金属蛋白酶。这些底物可用于设计试剂来成像动物和体内的蛋白水解作用。 人类。相同的底物也可用于制造靶向药物输送载体。最后，所有 来自研究、计算工具、结果、预测、蛋白质组分析和 解释将存放在我们的 Proteolysis MAP 网站 (www.proteothesis.org) 上，供科学界使用 和医学界。