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）是胶原蛋白、层粘连蛋白、纤连蛋白和蛋白聚糖的复杂网络，其提供细胞可以在其上粘附、分化和增殖的表面。ECM的缺陷是多种疾病的根本原因。ECM介导内皮细胞极性，并且在正常条件下可以抑制癌前转化为肿瘤状态。我们正在构建人工的，从头胶原蛋白为基础的矩阵使用分层计算方法。这些基质将在实验室中进行物理表征，并用于探测ECM中化学和空间组织对粘附细胞肿瘤形成潜力的作用。我们正在使用两个阶段，计算策略来构建人工ECM。一项关键技术是ProtCAD（蛋白质计算机自动设计），这是我们实验室专门为计算蛋白质设计开发的软件平台。在第一阶段，短胶原蛋白样模块的序列被设计成独立组装成具有程序稳定性和特异性的三聚体。然后，这些模块使用柔性肽接头共价连接，以促进受控的高阶结构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，我们的计算策略很可能会成功。合成ECM将用于生物医学研究和转化应用。哺乳动物细胞将在各向异性的自组装纳米结构基质上生长，以测定对细胞极性、细胞骨架取向和形态学的影响。我们将探索人工基质在各种致癌信号存在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。 成功设计的基质将被应用于工程更安全的人工组织。 公共卫生相关性：细胞外基质是一种复杂的蛋白质网络，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、骨和皮肤疾病、自身免疫性疾病如狼疮和广泛的癌症有关。人工纳米尺度的基质将有助于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。