Novel Mechanisms of Regenerative Tissue Repair

再生组织修复的新机制

基本信息

批准号：
10579954
负责人：
Sundeep G Keswani
金额：
$ 37.24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579954
关键词：
Address Adoptive Transfer Adult Affect Anti-Inflammatory Agents Attenuated Benchmarking Binding Proteins Biological Biomimetics CD4 Positive T Lymphocytes CD44 gene Cell Communication Cells Cicatrix Data Deposition Dermal Economic Burden Engineering Extracellular Matrix FOXP3 gene Fibroblasts Fibrosis Goals Health Healthcare Human Hyaluronan Hydrogels Immunity In Vitro Inflammation Injury Interleukin-10 Interleukin-4 Knowledge Lymphocyte Lymphocyte Subset Mediating Mediator Mission Molecular Molecular Weight Morbidity - disease rate Mus Outcome Patients Phase Phenotype Physiology Pre-Clinical Model Production Regulation Regulatory T-Lymphocyte Reporter Reporting Research Research Personnel Risk Role SCID Mice Severe Combined Immunodeficiency Signal Transduction Skin injury Skin wound healing System T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Translating Wound models angiogenesis antifibrotic treatment biobank clinical application cytokine design fetal healing improved in vivo mass spectrometric imaging mouse model neovascularization novel postnatal pre-clinical prevent psychosocial reconstitution regenerative regenerative tissue repaired response to injury skin wound spatiotemporal therapeutically effective tissue repair wound wound healing wound treatment

项目摘要

PROJECT SUMMARY Postnatal dermal injuries heal with scars, resulting in major health, psychosocial and economic burdens. Our team has studied the mechanisms of fetal regenerative tissue repair with the ultimate goal to develop anti- fibrotic therapies. In pursuit of this mission and with previous R01 support, our team has (i) found that IL-10 is a key regulator of fetal wound repair and promotes scarless healing, (ii) replicated the fetal scarless phenotype by application of IL-10 on postnatal dermal wounds, (iii) revealed new mechanisms that control extracellular matrix (ECM) remodeling and neovascularization via high molecular weight hyaluronan (HMW-HA) signaling, (iv) demonstrated that HMW-HA drives T lymphocyte-mediated IL-10 expression, (v) recently reported a temporal influx of predominantly CD4+ T lymphocytes in murine skin wounds that correlated with the proliferative and remodeling phases of wound healing, and (vi) obtained evidence that reconstitution of immunity by adoptive transfer of functional CD4+ T lymphocytes in severe combined immune deficient mice significantly reduced inflammation, decreased fibrosis, and healed post-injury dermal wounds with less scarring. While our collective data strongly suggest a concerted HMW-HA-mediated IL-10-dependent crosstalk between fibroblast cells and mobilized T lymphocytes in response to injury, little is known about the identity of IL-10-producing CD4+ T lymphocyte subsets and how they contribute to dermal wound repair outcomes. We hypothesize that: (a) CD4+ lymphocyte subsets differentially regulate postnatal dermal scarring via IL-10- dependent signaling and (b) HA and the hyaladherins transduce signals to drive IL-10 production by CD4+ lymphocytes, which reduces scarring risks. To obtain experimental evidence that supports our hypothesis and provides compelling clues to design effective anti-scar therapies, we propose three specific aims. In aim 1, we will identify the mechanisms by which IL-10-producing CD4+ T lymphocyte subsets regulate inflammation, ECM formation and angiogenesis to reduce scar formation in vitro and in vivo. In this and subsequent aims, we will use unique 10Bit4 mouse models engineered with a triple reporter system - IL-4 (RFP), Il-10 (CD90.1), and Foxp3 (GFP) - to unambiguously assess the requirement of different T lymphocyte subsets presumed to transduce anti-scar functions. In aim 2, we will investigate how HA regulates CD4+ lymphocyte production of IL-10 via CD44 signaling, and determine how HA-stabilizing hyaladherins influence this signaling cascade. Finally in aim 3, we will determine if HA-mediated endogenous IL-10 production can direct adult fibroblasts toward a fetal-like regenerative phenotype and if this signaling can influence human scarring phenotypes. Using our gained knowledge, we will then optimize a translational HMW-HA-based hydrogel treatment system to promote stable IL-10 production by CD4+ lymphocytes in dermal wounds and test its effects on scarring outcomes in a preclinical wound healing model. Overall, the proposed aims will reveal new CD4+ lymphocyte physiology in wound healing and lead to a novel translational treatment paradigm to mitigate dermal scarring.

项目概要产后皮肤损伤会留下疤痕，导致严重的健康、心理和经济负担。我们的研究小组研究了胎儿再生组织修复的机制，最终目标是开发抗纤维化疗法。为了实现这一使命并在之前的 R01 支持下，我们的团队 (i) 发现 IL-10 胎儿伤口修复的关键调节剂并促进无疤痕愈合，(ii) 复制胎儿无疤痕表型通过在产后皮肤伤口上应用 IL-10，(iii) 揭示了控制细胞外的新机制通过高分子量透明质酸 (HMW-HA) 信号传导进行基质 (ECM) 重塑和新血管形成， (iv) 证明 HMW-HA 驱动 T 淋巴细胞介导的 IL-10 表达，(v) 最近报道了小鼠皮肤伤口中主要 CD4+ T 淋巴细胞的暂时流入与伤口愈合的增殖和重塑阶段，并且（vi）获得了重建的证据通过功能性 CD4+ T 淋巴细胞过继转移严重联合免疫缺陷小鼠的免疫显着减少炎症，减少纤维化，并用更少的时间治愈受伤后的真皮伤口疤痕。虽然我们的集体数据强烈表明 HMW-HA 介导的 IL-10 依赖性串扰是一致的成纤维细胞和动员的 T 淋巴细胞之间对损伤的反应，人们对它们的身份知之甚少。产生 IL-10 的 CD4+ T 淋巴细胞亚群及其如何促进真皮伤口修复结果。我们假设：(a) CD4+ 淋巴细胞亚群通过 IL-10- 差异调节产后真皮疤痕 (b) HA 和玻璃粘着蛋白转导信号以驱动 CD4+ 产生 IL-10 淋巴细胞，从而降低疤痕风险。获得支持我们假设的实验证据为设计有效的抗疤痕疗法提供了令人信服的线索，我们提出了三个具体目标。在目标 1 中，我们将确定产生 IL-10 的 CD4+ T 淋巴细胞亚群调节炎症、ECM 的机制形成和血管生成，以减少体外和体内疤痕形成。在这个目标和后续目标中，我们将使用采用三重报告系统设计的独特 10Bit4 小鼠模型 - IL-4 (RFP)、IL-10 (CD90.1) 和 Foxp3 (GFP) - 明确评估不同 T 淋巴细胞亚群的需求，推测转导抗疤痕功能。在目标 2 中，我们将研究 HA 如何调节 CD4+ 淋巴细胞的产生 IL-10 通过 CD44 信号传导，并确定 HA 稳定透明粘蛋白如何影响该信号级联。最后，在目标 3 中，我们将确定 HA 介导的内源性 IL-10 的产生是否可以指导成体成纤维细胞朝向类似胎儿的再生表型，以及这种信号是否可以影响人类疤痕表型。利用我们所获得的知识，我们将优化基于 HMW-HA 的转化水凝胶处理系统促进真皮伤口中 CD4+ 淋巴细胞稳定产生 IL-10 并测试其对疤痕形成的影响临床前伤口愈合模型的结果。总体而言，拟议的目标将揭示新的 CD4+ 淋巴细胞伤口愈合中的生理学，并导致一种新的转化治疗范例，以减轻真皮疤痕。