Study and Application of Collagen Mimetic Peptide-Collagen Hybridization

胶原模拟肽-胶原杂交的研究及应用

• 批准号: 8031781
• 负责人: Michael S Yu
• 金额: $ 35.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-11 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8031781
• 关键词: 3-Dimensional; Affect; Affinity; Angiogenic Factor; Architecture; Behavior; Binding; Binding Sites; Biocompatible; Biocompatible Materials; Blood capillaries; Cell-Matrix Junction; Cells; Cellular Structures; Chemicals; Chronic Disease; Cicatrix; Clinical; Collaborations; Collagen; Collagen Type I; Complex; Cues; Development; Diagnosis; Diagnostic; Disease; Drug Delivery Systems; Employment; Endothelial Cells; Engineering; Environment; Event; Extracellular Matrix; FDA approved; Fibrosis; Goals; Grant; Hybrids; Image; In Vitro; Laminin; Mammals; Metabolic; Methods; Modification; Molecular; Morphogenesis; Nature; Organ; Paper; Pathologic; Pathway interactions; Pattern; Pennsylvania; Peptides; Polymers; Process; Production; Property; Proteins; Research; Research Project Grants; Signal Transduction; Stimulus; System; Technology; Testing; Therapeutic; Tissue Engineering; Tissues; Transplantation; United States National Institutes of Health; Universities; Work; base; capillary; cell behavior; design; imaging modality; implantation; improved; in vivo; in vivo regeneration; mimetics; new technology; next generation; novel strategies; programs; repaired; scaffold; self assembly; success; tissue regeneration; tissue support frame; tumor; tumor growth

DESCRIPTION (provided by applicant): Collagens, the most abundant protein in mammals, provide a structural framework during tissue development and repair, and their structural and metabolic abnormalities are common to many chronic diseases (e.g. fibrosis and tumor growth). A simple synthetic molecule with selective binding affinity to collagen may offer new pathways for diagnosis and treatment of such diseases as well as facilitate production of functionalized collagen scaffolds for new and improved biomaterials applications in tissue engineering and drug delivery. This project focuses on i) developing new synthetic collagen mimetic peptides (CMPs) that bind specifically to natural collagen by a unique helix hybridization mechanism, and ii) creating collagen-based tissue engineering scaffolds that display morphogenic signals in a spatially and temporally defined manner. The long-term goals are to develop diagnostic and therapeutic methods that target disease-related fibrosis and to develop revolutionary methods for encoding cell-instructive signals onto collagen scaffolds in vivo for tissue regeneration and in vitro for transplantation therapy. As part of the efforts in achieving these long-term goals, the following specific aims are set forth in the proposed work: 1) Acquire a molecular level understanding of CMP-collagen hybridization interactions, 2) Develop new CMP architectures that will allow precise patterning of collagen scaffolds, and 3) Demonstrate spatial control of angiogenic events in collagen scaffolds with collagen- bound morphogenic factors by employment of CMPs. In aim 1, a key hypothesis for CMP-collagen binding- that CMPs interact with the unfolded domains of collagen molecules by forming a hybrid triple helical complex- is tested by identifying molecular factors that affect binding events such as CMP's helical propensity and collagen's level of unfolding, and by isolating and studying the biophysical properties of CMP-collagen complexes. In aim 2, new methods for spatio-temporal modification of collagen scaffolds are proposed that involve the design and synthesis of caged-CMPs that can be photo-triggered to fold and bind to collagen; the photo-triggered binding event will be investigated in the context of 2D and 3D collagen scaffold patterning. And aim 3 attempts to control spatial organization of microvasculature formation in collagen scaffolds (for both in vivo and in vitro systems) by employment of CMPs and caged-CMPs conjugated to cell-instructive molecules. In the long run, completion of the proposed work will allow engineering of microvasculature networks for re-vascularizing native ischemic tissues as well as vascularizing ex-vivo engineered tissues. It may also offer new pathways for imaging pathologic scar tissue as well as facilitate production of functionalized collagen scaffolds for new and improved biomaterials applications in tissue engineering and drug delivery. PUBLIC HEALTH RELEVANCE: This research project focuses on developing new synthetic molecules with a unique binding affinity to natural collagens, and creating collagen-based, cell-instructive tissue scaffolds that can control microvasculature network formation. This may allow revascularizing native ischemic tissues as well as vascularizing ex-vivo engineered tissues. In addition, collagen-targeting molecules may offer new pathways for imaging and treatment of pathological scar tissues such as fibrosis, arterial plaques, and tumors.

描述(申请人提供)：胶原蛋白是哺乳动物中含量最丰富的蛋白质，在组织发育和修复过程中提供结构框架，其结构和代谢异常在许多慢性疾病(如纤维化和肿瘤生长)中很常见。一种与胶原具有选择性结合亲和力的简单合成分子可能为此类疾病的诊断和治疗提供新的途径，并有助于制备功能化的胶原支架，用于组织工程和药物释放方面的新型和改进的生物材料应用。该项目的重点是：1)开发新的人工合成的胶原蛋白模拟肽(CMPS)，通过独特的螺旋杂交机制与天然胶原蛋白特异性结合；2)创建以胶原蛋白为基础的组织工程支架，以空间和时间定义的方式显示形态发生信号。长期目标是开发针对疾病相关纤维化的诊断和治疗方法，并开发革命性的方法，将细胞指示信号编码到体内胶原支架上，用于组织再生和体外移植治疗。作为实现这些长期目标的努力的一部分，拟议的工作中提出了以下具体目标：1)从分子水平了解CMP-胶原杂交相互作用，2)开发新的CMP结构，使胶原支架能够精确构型，3)通过使用CMPS展示胶原结合形态生成因子对胶原支架中血管生成事件的空间控制。在目标1中，通过确定影响结合事件的分子因素，如cMP的螺旋倾向和胶原的展开水平，以及分离和研究cMP-胶原复合体的生物物理性质，验证了CMP-胶原结合的一个关键假设-CMPS通过形成杂化的三螺旋复合体与胶原分子的未折叠区域相互作用。在目标2中，提出了胶原支架时空修饰的新方法，包括设计和合成可被光触发折叠并结合到胶原上的笼状CMPS；光触发结合事件将在2D和3D胶原支架构图的背景下进行研究。目的3尝试通过使用CMPS和连接到细胞指导分子的笼状CMPS来控制胶原支架(包括体内和体外系统)中微血管形成的空间组织。从长远来看，拟议工作的完成将使微血管网络的工程成为可能，使天然缺血组织重新血管化，并使体外工程组织血管化。它还可能为病理性瘢痕组织的成像提供新的途径，并促进功能化胶原支架的生产，用于组织工程和药物输送方面的新型和改进的生物材料应用。 与公共健康相关：该研究项目专注于开发与天然胶原蛋白具有独特结合亲和力的新合成分子，并创建基于胶原蛋白的、可控制微血管网络形成的具有细胞指导作用的组织支架。这可能会使天然的缺血组织再血管化以及体外工程组织的血管再血管化。此外，胶原靶向分子可能为病理性瘢痕组织的成像和治疗提供新的途径，如纤维化、动脉斑块和肿瘤。