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（由申请人提供）：胶原蛋白是哺乳动物中最丰富的蛋白质，在组织发育和修复过程中提供了一个结构框架，其结构和代谢异常对于许多慢性疾病（例如纤维化和肿瘤生长）来说是常见的。具有与胶原蛋白具有选择性结合亲和力的简单合成分子可能会为诊断和治疗此类疾病提供新的途径，并促进在组织工程和药物递送中的新生物材料应用中的功能化胶原支架。该项目的重点是I）开发新的合成胶原蛋白模拟肽（CMP），该胶原蛋白肽（CMP）通过独特的螺旋杂交机制专门与天然胶原蛋白结合，ii）创建基于胶原蛋白的组织工程支架，以空间和时间定义的方式显示形态发生的信号。长期目标是开发针对疾病相关的纤维化的诊断和治疗方法，并开发用于在体内编码细胞结构信号到体内胶原蛋白支架上的革命性方法，以进行组织再生和体外用于移植治疗。 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 CMP。 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.在AIM 2中，提出了胶原蛋白支架时空修饰的新方法，该方法涉及笼子CMP的设计和合成，这些方法可以触发以折叠并与胶原蛋白结合；照片触发的结合事件将在2D和3D胶原支架图案的背景下进行研究。 AIM 3试图通过使用CMP和CMPS和笼中的CMP与细胞结构分子相结合的胶原蛋白支架（用于体内和体外系统）中微脉管形成的空间组织。 从长远来看，拟议的工作的完成将允许工程化微脉管网络，以重新血管性本地缺血组织以及血管化的前体内工程组织。它还可以提供新的途径，用于成像病理疤痕组织，并促进在组织工程和药物输送中的新生物材料应用中的功能化胶原支架。 公共卫生相关性：该研究项目着重于开发具有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细胞结构组织脚手架，可以控制微脉管网络形成。这可能允许血运重建的本地缺血组织以及血管前体工程组织。此外，靶向胶原蛋白的分子可能会为病理疤痕组织（例如纤维化，动脉斑块和肿瘤）进行成像和治疗提供新的途径。