Computational Design of a Synthetic Extracellular Matrix

合成细胞外基质的计算设计

• 批准号: 7849244
• 负责人: Vikas Nanda
• 金额: $ 184.32万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849244
• 关键词: Autoimmune Diseases; Biocompatible Materials; Biological Assay; Biomedical Research; Cancer Biology; Cell Polarity; Cell Proliferation; Cells; Chemicals; Collagen; Complex; Computer software; Computers; Defect; Disease; Endothelial Cells; Engineering; Extracellular Matrix; Fibronectins; Generations; Higher Order Chromatin Structure; Intestines; Laboratories; Laminin; Link; Lupus; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Oncogenic; Peptides; Proliferating; Proteins; Proteoglycan; Role; Signal Transduction; Specificity; Staging; Surface; System; Technology; Tissue Engineering; Tissues; abstracting; base; bone; design; flexibility; nanoscale; nanostructured; neoplastic; programs; public health relevance; skin disorder; tumor

DESCRIPTION (Provided by the applicant) Abstract: The extracellular matrix (ECM) is a complex network of collagens, laminins, fibronectins and proteoglycans that provides a surface upon which cells can adhere, differentiate and proliferate. Defects in the ECM are the underlying cause of a wide spectrum of diseases. The ECM mediates endothelial cell polarity and under normal conditions can suppress pre-oncogenic transitions to a neoplastic state. We are constructing artificial, de novo collagen-based matrices using a hierarchic computational approach. These matrices will be physically characterized in the laboratory and used to probe the role of chemical and spatial organization in the ECM on the tumor forming potential of adhered cells. We are using a two-stage, computational strategy to construct an artificial ECM. A key technology is protCAD (protein Computer Automated Design), a software platform developed in our laboratory specifically for computational protein design. In the first stage, the sequences of short collagen-like modules are designed to independently assemble into trimers of programmed stability and specificity. These modules are then covalently connected using flexible peptide linkers to facilitate the selfassembly of controlled higher-order structures such as networks and fibrils. Encouraging experimental characterization of the first generation collagen designs suggests that our computational strategy is likely to succeed. Synthetic ECMs will be useful in biomedical research and translational applications. Mammalian cells will be grown on anisotropic, self-assembling nanostructured matrices to assay effects on cell polarity, cytoskeletal orientation and mophology. We will explore the ability of artificial matrices to suppress cell proliferation in the presence of various oncogenic signals. This will provide a powerful system for studying molecular aspects of the matrix biology of cancer. Successfully designed matrices will be applied to engineering safer artificial tissues. Public Health Relevance: The extracellular matrix is a complex network of proteins that provides a platform for cells to adhere on and assemble into complex tissues. Defects in the extracellular matrix are linked to a number of bowel, bone and skin diseases, autoimmune disorders such as Lupus and a broad range of cancers. Artificial, nano-scale matrices will help us study the role of the matrix in disease, and provide safe biomaterials for tissue engineering.

描述（由申请人提供） 摘要：细胞外基质（ECM）是由胶原蛋白、层粘连蛋白、纤连蛋白和蛋白聚糖组成的复杂网络，为细胞粘附、分化和增殖提供了表面。 ECM 缺陷是多种疾病的根本原因。 ECM 介导内皮细胞极性，在正常条件下可以抑制致癌前向肿瘤状态的转变。我们正在使用分层计算方法构建人工的、从头开始的胶原蛋白基质。这些基质将在实验室进行物理表征，并用于探讨 ECM 中化学和空间组织对粘附细胞肿瘤形成潜力的作用。我们使用两阶段计算策略来构建人工 ECM。一项关键技术是protCAD（蛋白质计算机自动化设计），这是我们实验室开发的专门用于计算蛋白质设计的软件平台。在第一阶段，短胶原蛋白样模块的序列被设计为独立组装成具有程序稳定性和特异性的三聚体。然后使用柔性肽接头将这些模块共价连接，以促进受控高阶结构（例如网络和原纤维）的自组装。第一代胶原蛋白设计的令人鼓舞的实验表征表明我们的计算策略可能会成功。合成 ECM 将在生物医学研究和转化应用中发挥作用。哺乳动物细胞将在各向异性、自组装纳米结构基质上生长，以分析对细胞极性、细胞骨架方向和形态的影响。我们将探索人工基质在存在各种致癌信号的情况下抑制细胞增殖的能力。这将为研究癌症基质生物学的分子方面提供一个强大的系统。 成功设计的基质将应用于工程更安全的人造组织。 公共健康相关性：细胞外基质是一个复杂的蛋白质网络，为细胞粘附并组装成复杂组织提供了平台。细胞外基质的缺陷与许多肠道、骨骼和皮肤疾病、狼疮等自身免疫性疾病以及多种癌症有关。人造纳米基质将帮助我们研究基质在疾病中的作用，并为组织工程提供安全的生物材料。