Engineered Matrix Mimetics: Novel Therapies for Wound Repair

工程基质模拟物：伤口修复的新疗法

基本信息

批准号：
7799196
负责人：
Denise C Hocking
金额：
$ 31.14万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-05 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7799196
关键词：
Affect Antibodies Binding Binding Sites Biochemical Biological Biological Assay Biomedical Engineering Blocking Antibodies Blood flow Burn injury Bypass Cell Adhesion Cell Communication Cell Count Cell Cycle Progression Cell Migration Pathway Cell Proliferation Cell Surface Receptors Cell physiology Cell surface Cells Chronic Cicatrix Clinical Collagen Collagen Type I Complex Data Deposition Dermal Development Diabetes Mellitus Diabetic mouse Elderly Engineering Environment Event Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibronectins Gel Gelatin Genetic Glycoproteins Goals Growth Healed Heparan Sulfate Proteoglycan Heparin Binding Human Immunofluorescence Microscopy Impaired wound healing In Situ Infection Infection prevention Injury Integrin Binding Integrins Kidney Diseases Lead Length Ligand Binding Ligation Limb structure Liquid substance Mechanics Mediating Methods Molecular Conformation Mutate Myofibroblast Normal tissue morphology Null Lymphocytes Organ Peptides Plasma Play Process Protein Binding Protein Engineering Proteins Proteoglycan Recombinant Proteins Recombinants Risk Role Series Signal Transduction Site Skin Technology Tensile Strength Testing Therapeutic Thick Tissues Topical agent Topical application Vasodilation Work Wound Healing analog base blood product cell growth cell motility design and construction diabetic rat healing improved in vivo injured keratinocyte meetings migration mimetics mouse model mutant novel novel strategies novel therapeutic intervention polymerization public health relevance receptor reconstitution response scaffold small molecule success therapeutic protein therapy design tissue regeneration wound

项目摘要

DESCRIPTION (provided by applicant): Tissue injury initiates a series of temporally- and spatially-integrated events requiring interactions between cells and proteins in the surrounding extracellular matrix (ECM). Many factors can delay wound healing, including infection, advanced age, diabetes, and renal disease. Disruptions in the healing process can lead to non-healing, chronic wounds or conversely, result in the development of fibrotic scars that compromise organ function. The ECM of wounds is composed of collagens, glycoproteins, and proteoglycans. These proteins provide an array of cell adhesion sites, cell migration pathways, and proliferation signals to cells, and impart mechanical stability to the healing wound. Fibronectin (FN) is a principal component of the ECM. Soluble FN molecules are assembled into the ECM as insoluble, fibrillar strands via a cell-dependent process. In turn, the interaction of cells with the ECM form of FN stimulates cell functions critical for tissue repair. FN matrix assembly also promotes collagen matrix deposition and increases tissue tensile strength. FN matrix assembly is normally rapidly up- regulated following tissue injury, while reduced FN matrix deposition is associated with chronic wounds. Hence, therapeutic approaches that circumvent diminished FN matrix assembly by providing injured cells with synthetic ECM-like FNs may accelerate wound healing. In this project, we will determine the role of FN matrix polymerization in normal wound repair and understand how this process may be altered in chronic wounds. Additionally, we will develop recombinant FN matrix mimetics as accelerators of tissue regeneration and ask whether these engineered proteins promote tissue repair in a mouse model of impaired wound healing. This novel therapeutic approach should eliminate the need for cell-dependent FN ECM assembly in the chronic wound and thus, promote wound repair by providing injured tissues with key ECM FN-specific signals and structural information. New treatment approaches are needed to rapidly close burns and chronic wounds to decrease the risk of infection, prevent fluid loss, and promote the natural healing process. We envision the clinical use of these mimetics as a means to rapidly up-regulate cell function and tissue mechanics in chronic, non-healing wounds. PUBLIC HEALTH RELEVANCE: Many factors can delay wound healing, including infection, advanced age, diabetes, and renal disease. New treatment approaches are needed to rapidly close burns and chronic wounds to decrease the risk of infection, prevent fluid loss, and promote the natural healing process. Here, we will develop the use of recombinant extracellular matrix analogs as a novel therapy to rapidly up-regulate cell function and tissue mechanics in chronic, non-healing wounds.

描述（由申请人提供）：组织损伤引发了一系列时间和空间集成事件，这些事件需要周围细胞外基质（ECM）中细胞与蛋白质之间的相互作用。许多因素可以延迟伤口愈合，包括感染，高龄，糖尿病和肾脏疾病。愈合过程中的破坏会导致非治疗，慢性伤口或相反的伤口导致损害器官功能的纤维化疤痕的发展。伤口的ECM由胶原蛋白，糖蛋白和蛋白聚糖组成。这些蛋白质提供了一系列细胞粘附位点，细胞迁移途径和向细胞的增殖信号，并赋予机械稳定性。纤连蛋白（FN）是ECM的主要成分。可溶性FN分子通过细胞依赖性过程作为不溶性纤维链组装成ECM。反过来，细胞与FN的ECM形式的相互作用刺激细胞对组织修复至关重要。 FN基质组件还促进胶原基质沉积并增加组织拉伸强度。 FN基质组件通常在组织损伤后迅速上调节，而降低的FN基质沉积与慢性伤口有关。因此，通过为受伤的细胞提供合成的ECM样FN来缩小FN基质组件的治疗方法可能会加速伤口愈合。在该项目中，我们将确定FN基质聚合在正常伤口修复中的作用，并了解如何在慢性伤口中改变此过程。此外，我们将开发重组FN基质Mimetics作为组织再生的加速器，并询问这些工程蛋白是否在伤口愈合受损的小鼠模型中促进组织修复。这种新型的治疗方法应消除慢性伤口中对细胞依赖性FN ECM组装的需求，从而通过为受伤的组织提供关键的ECM FN特异性信号和结构信息来促进伤口修复。需要采用新的治疗方法来迅速闭合烧伤和慢性伤口，以降低感染的风险，防止液体流失并促进自然愈合过程。我们设想这些模拟物的临床用途是快速上调慢性，非治疗伤口中细胞功能和组织力学的手段。公共卫生相关性：许多因素会延迟伤口愈合，包括感染，高龄，糖尿病和肾脏疾病。需要采用新的治疗方法来迅速闭合烧伤和慢性伤口，以降低感染的风险，防止液体流失并促进自然愈合过程。在这里，我们将开发重组细胞外基质类似物作为一种新型疗法，以迅速上调慢性，非治疗伤口的细胞功能和组织力学。