Regenerative wound healing via inflammation-modulating biomaterials

通过炎症调节生物材料实现伤口再生愈合

基本信息

批准号：
8107808
负责人：
Ellen s. Heber-Katz
金额：
$ 43.77万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107808
关键词：
Address Agonist Amphibia Backcrossings Beds Binding Biocompatible Materials Biological Biological Assay Biological Markers Biomimetic Materials C57BL/6 Mouse Cartilage Cell Culture Techniques Cell Cycle Regulation Cell physiology Cell-Matrix Junction Cells Chemicals Chromosome Mapping Cicatrix Clinical Collaborations Complex Coupled Cytotoxic T-Lymphocytes Degradation Pathway Dose Ear Effectiveness Encapsulated Enzymes Family Fibroblasts Future Glycolysis Goals Growth Healed Human Hydrogels Hydroxylation In Situ In Vitro Inbreeding Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Kinetics Knowledge Laboratories Ligation Liver Luciferases Mammals Matrix Metalloproteinases Mediating Mediator of activation protein Medical Medicine Metabolic Metabolism Methods Modality Molecular Mouse Strains Mus Natural regeneration Organ Oryctolagus cuniculus Outcome Pathway interactions Patient Care Peptides Pharmaceutical Preparations Polymers Process Procollagen-Proline Dioxygenase Proteins Reaction Reporter Role Site Testing Therapeutic Agents Time Tissues Topical agent Toxic effect Transcriptional Regulation Translating Ubiquitination Up-Regulation Wound Healing angiogenesis appendage base blastema cartilage regeneration design healing hypoxia inducible factor 1 in vivo inhibitor/antagonist insight limb regeneration migration mouse model novel protein expression reconstitution regenerative response skills success tissue regeneration transcription factor ubiquitin-protein ligase wound

项目摘要

DESCRIPTION (provided by applicant): It is well known that prolonged inflammation hinders the optimal goal of wound repair, namely prompt closure of the wound with minimal scarring. However, the objective of tissue regeneration (as opposed to wound repair) is to reconstitute and replace damaged tissue with a functional biological replica of the lost tissue without scarring. In this latter case, the role of inflammation is not well established for the simple reason that most mammals including humans have rarely demonstrated any capacity for regeneration (with the exception of the liver) precluding experimental approaches. Based upon our preliminary observations in a mouse model of appendage injury, this proposal will address the possibility that enhancing at least some aspects of inflammation will re-direct wound healing towards regeneration. We will also examine the use of novel biomaterials to locally harness key aspects of the inflammatory response and facilitate tissue regeneration. Ear whole closure, as seen in rabbits and in the inbred MRL mouse strain is considered to be a mammalian example of regeneration similar to limb regeneration in amphibians. Ear holes close completely with the replacement of cartilage and without scarring. In this proposal, we present in-vitro and in-situ evidence that the wound site during this regenerative response is pro-inflammatory and that pharmacological up- regulators of inflammation induce regeneration in otherwise non-regeneration competent mice. Inflammation has been shown to be regulated by the transcription factor HIF1a and we will focus on HIF1a up-regulation in C57BL/6 mice to further explore its role in the regenerative response. Since HIF1a is modulated at the protein level and its degradation is initiated by hydroxylation accomplished by prolyl hydroxylases (PHDs), we will examine several inhibitors of HIF1a degradation including a PHD inhibitor, a direct HIF1a hydroxylation inhibitor and an inhibitor of ubiquination. These molecules will be screened for activity in HIF-luciferase reporter mice and their cells in-vitro as 1) topical agents or soluble injectants into the wound site or administered systemically and 2) coupled to a biomaterial. Given that HIF activity regulates as much as 10% of all cellular functions and especially the metabolic state and inflammation, it is important that HIF-activating drugs be present only at the wound site and in a controlled manner. Novel in- situ forming macromolecular biomaterials will be designed with the goal of fine control, both spatial and temporal, of HIF levels at the wound site. We envision that this approach of mimicking the complex tissue microenvironment of a healing wound will allow for biomaterial degradation accompanied by tissue regeneration, leading in the future to new clinical modalities for tissue regeneration. PUBLIC HEALTH RELEVANCE: Achieving predictable regeneration of damaged tissues and organs is a major goal of medicine. By studying the remarkable ability of the MRL mouse to heal injuries and the role of inflammation in this process, we will gain insight into methods to help translate this knowledge into patient care. In particular, we will examine the role of implantable "smart" biomaterials that release regeneration-specific drugs that regulate metabolism and inflammation and are under biological control.

描述（由申请人提供）：众所周知，长时间的炎症阻碍了伤口修复的最佳目标，即以最小的疤痕迅速闭合伤口。但是，组织再生的目的（与伤口修复相反）是用失去组织的功能性生物学复制品重新构建和代替受损的组织，而不会造成疤痕。在后一种情况下，由于包括人类在内的大多数哺乳动物很少证明任何再生能力（肝脏除外）排除实验方法的简单原因，炎症的作用并不是很好的。基于我们在肢体损伤的小鼠模型中的初步观察结果，该建议将解决至少提高炎症某些方面的可能性，将使伤口愈合重新定向到再生。我们还将检查新型生物材料在局部利用炎症反应的关键方面，并促进组织再生。如在兔子和近交小鼠菌株中所见，耳朵整体闭合被认为是两栖动物类似于肢体再生的哺乳动物例子。耳孔完全封闭，随着软骨的替换而没有疤痕。在该提案中，我们提供了现场和原位证据，表明这种再生反应中的伤口部位是促炎性的，并且炎症的药理学上的调节剂会诱导其他非再生能力小鼠的再生。炎症已被证明受转录因子HIF1A的调节，我们将重点介绍C57BL/6小鼠的HIF1A上调，以进一步探索其在再生反应中的作用。由于HIF1A在蛋白水平上进行调节，其降解是通过羟基羟化酶（PHDS）实现的羟基化引发的，因此我们将检查HIF1A降解的几种抑制剂，包括PHD抑制剂，包括直接的HIF1A HIF1A羟基化抑制剂和ubiquiner的抑制剂。这些分子将在HIF-荧光素酶报告基因小鼠及其细胞中的活性筛选为1）局部或可溶的注射剂或系统地施用，以及2）与生物材料偶联。鉴于HIF活性调节了所有细胞功能的10％，尤其是代谢状态和炎症，因此重要的是，仅在伤口部位和受控方式才出现HIF激活药物。新型的内形成大分子生物材料的设计将以伤口部位的HIF水平进行精细控制，以实现空间和时间的良好控制。我们设想，这种模仿愈合伤口的复杂组织微环境的方法将允许生物材料降解并伴有组织再生，将来导致了新的临床复兴临床方式。公共卫生相关性：实现受损组织和器官的可预测再生是医学的主要目标。通过研究MRL小鼠治愈损伤的显着能力以及炎症在此过程中的作用，我们将深入了解将这种知识转化为患者护理的方法。特别是，我们将研究可植入的“智能”生物材料的作用，这些生物材料释放了调节代谢和炎症的再生特异性药物，并且受到生物控制。