Does Inflammation Enhance Rengeneration?

描述（由申请方提供）：众所周知，长期炎症会阻碍伤口修复的最佳目标，即伤口迅速闭合，瘢痕形成最少。然而，组织再生（与伤口修复相反）的目的是重建受损的组织，并用功能性生物复制品替代丢失的组织，而不会留下疤痕。在后一种情况下，炎症的作用还没有很好地确定，原因很简单，大多数哺乳动物，包括人类，很少表现出任何再生能力（肝脏除外），排除了实验方法。根据我们在小鼠附件损伤模型（MRL小鼠的耳孔闭合）中的观察结果，该提议将解决以下反直觉的可能性：增强炎症的至少某些方面将使伤口愈合重新导向再生。我们还将研究使用新型生物材料来局部利用炎症反应的关键方面并促进组织再生。MRL小鼠已被证明是多种组织类型的强大再生者，我们一直注意到再生伴随着损伤部位的强烈和长期炎症。给予抗炎性COX 2抑制剂美洛昔康可抑制MRL耳孔闭合，表明炎症可能在功能上参与了耳器再生。我们直接测试了这种可能性在非再生C57 BL/6小鼠局部应用促炎药物咪喹莫特，一种toll样受体（TLR）配体，在两个伤口模型的损伤部位：耳孔愈合和手指截肢。在这两种情况下，积极的再生结果随之而来。在本提案中，我们将1）检查参与MRL再生反应的TLR，2）尝试使用局部应用的选择TLR配体刺激那些主要TLR，以在非再生C57 BL/6小鼠中引发再生反应。炎症和再生反应的水平将在转录物、蛋白质、细胞和组织水平上确定。3)我们将不仅局部应用这些TLR配体，而且将产生化学共轭化合物到生物材料上。后者将为我们提供一种新型的可注射原位形成的大分子生物材料（NCL水凝胶），不仅可用于表面损伤，而且可用于深部损伤。我们设想，这种模拟愈合伤口的炎症微环境的方法将允许伴随组织再生的生物材料降解，从而在未来导致新的组织再生临床模式。

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 observations in a mouse model of appendage injury (ear hole closure in the MRL mouse), this proposal will address the counter-intuitive 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. MRL mice have been shown to be robust regenerators of multiple tissue types and we have consistently noted that regeneration is accompanied by intense and prolonged inflammation at the injury site. Administration of the anti-inflammatory COX2 inhibitor meloxicam inhibits MRL ear hole closure suggesting that inflammation may be functionally involved in appendage regeneration. We directly tested this possibility in non-regenerating C57BL/6 mice by topically applying the pro-inflammatory drug imiquimod, a toll-like receptor (TLR) ligand, to injury sites in two wound models: ear hole healing and digit amputation. In both cases, a positive regenerative result ensued. In this proposal, we will 1) examine the TLRs involved in the MRL regenerative response and 2) attempt to stimulate those predominant TLRs using select TLR ligands applied topically to elicit a regenerative response in the non-regenerating C57BL/6 mouse. The level of inflammation and regenerative response will be determined at the transcript, protein, cellular and tissue levels. 3) We will apply those TLR ligands not only topically but will generate chemically conjugated compounds to a biomaterial. The latter will provide us with a novel injectable in-situ forming macromolecular biomaterial (NCL hydrogel) that can be used for injuries that are not only surface injuries but deep injuries as well. We envision that this approach of mimicking the inflammatory 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.