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：
8454537
负责人：
Ellen s. Heber-Katz
金额：
$ 40.55万
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/8454537
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 public health relevance 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.

描述（由申请人提供）：众所周知，长期炎症会阻碍伤口修复的最佳目标，即迅速闭合伤口并尽量减少疤痕。然而，组织再生（与伤口修复相反）的目标是用丢失组织的功能性生物复制品重建和替换受损组织，而不留疤痕。在后一种情况下，炎症的作用尚未明确，原因很简单，包括人类在内的大多数哺乳动物很少表现出任何再生能力（肝脏除外），排除了实验方法。根据我们对小鼠附肢损伤模型的初步观察，该提议将解决增强炎症的至少某些方面将重新引导伤口愈合走向再生的可能性。我们还将研究新型生物材料的使用，以局部利用炎症反应的关键方面并促进组织再生。耳朵整体闭合，如在兔子和近交 MRL 小鼠品系中所见，被认为是哺乳动物再生的例子，类似于两栖动物的肢体再生。更换软骨后耳孔完全闭合，不会留下疤痕。在本提案中，我们提出了体外和原位证据，表明再生反应期间的伤口部位是促炎性的，并且炎症的药理学上调剂可诱导其他无再生能力的小鼠的再生。炎症已被证明受到转录因子 HIF1a 的调节，我们将重点关注 C57BL/6 小鼠中 HIF1a 的上调，以进一步探讨其在再生反应中的作用。由于 HIF1a 在蛋白质水平上受到调节，并且其降解是通过脯氨酰羟化酶 (PHD) 完成的羟基化引发的，因此我们将研究几种 HIF1a 降解抑制剂，包括 PHD 抑制剂、直接 HIF1a 羟基化抑制剂和泛素化抑制剂。这些分子将在 HIF-荧光素酶报告小鼠及其细胞中进行体外活性筛选，作为 1) 局部制剂或可溶性注射剂进入伤口部位或全身给药，以及 2) 与生物材料偶联。鉴于 HIF 活性调节多达 10% 的所有细胞功能，尤其是代谢状态和炎症，因此 HIF 激活药物仅以受控方式存在于伤口部位非常重要。新型原位成型大分子生物材料的设计目标是在空间和时间上精细控制伤口部位的 HIF 水平。我们设想，这种模拟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随组织再生，从而在未来带来新的组织再生临床模式。