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.

项目摘要 蛋白水解途径几乎涉及每一种人类疾病，包括癌症、血栓形成， 关节炎、感染、炎症和阿尔茨海默病。许多这些分裂事件发生在 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（MMPs）。关于这些蛋白酶已经发表了超过40，000篇论文，“MMP”是 目前有400多个国家卫生研究院赠款。这部庞大的作品包含了重要的信息， 但在这一点上，任何单一的关于基质金属蛋白酶的出版物都只能逐步推进我们的知识。其实对于 “流行的”MMP，收集的许多信息是相互矛盾的，提出的问题多于答案。 然而，另一方面，基质甚至还没有被确定为近一半的MMP家族。 这个项目的长期目标是通过一个主要的 推进我们的理解的结构-功能的关系，指导基质金属蛋白酶的底物选择性。 为了实现这一目标，我们将研究MMP的结构和功能，在系统级。而不是试图 为了了解MMP如何切割底物，我们将定量描述家族中的每种蛋白酶如何切割底物， 识别并切割其底物。 该项目的具体目的是测试以下假设：1）每种特异性决定 MMP催化结构域内的位置对底物选择性做出不同的贡献，2） MMPs的生理（和病理生理）底物可以通过将知识放在子网站上来预测， 3）MMP血红素结合蛋白（HPX）结构域调节，但 不改变底物识别和选择性。 本研究的结果将为理解MMP的生物学功能提供必要的基础 和系统层面的病理学这项研究将揭示专业化和扩大的结构基础， 功能，这仍然是生物学中最重要的未回答的问题之一。这项工作还将揭示一个 因为底物是MMP活性的真实的下游效应物。 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，以在动物和哺乳动物中成像蛋白质水解。 人类相同的基质也可用于产生靶向药物递送载体。最后所有 来自研究的信息，计算工具，结果，预测，蛋白质组学分析和 解释将存放在我们的蛋白水解MAP网站（www.proteolysis.org）上，供科学家使用。 和医学界。