Immune and Genetic Controls of Tissue Regeneration in Mice and Humans

摘要/摘要 皮肤创伤给退伍军人带来了严重的健康问题，包括战时创伤、糖尿病足 溃疡、压疮和病理性疤痕形成。我们的目标是设计新的方法来刺激自我 修复机制，并促进人类无疤痕伤口愈合/完全组织再生。我们使用一种 功能丧失的小鼠遗传、异种共生(两只小鼠的循环系统 手术连接)、质量细胞术、流式细胞术、基因组学、谱系追踪和分子生物学 研究小鼠耳组织再生。我们之前的工作和目前的初步数据表明，在两个 不同的生理环境，皮肤分泌的SDF1调节瘢痕形成和组织之间的切换 再生。在目标1中，我们将研究SDF1如何促进瘢痕形成和纤维化。神经营养因子的典型受体 SDF1为CXCR4。损伤后，我们假设皮肤分泌的SDF1招募CXCR4+免疫细胞，这是 产生旁分泌因子，诱导成纤维细胞形成纤维组织和疤痕。招募的细胞类型将是 已定义并经过功能测试。在目标2中，我们将我们的发现直接转化为人类。而病理性疤痕 形成(瘢痕疙瘩和增生性瘢痕)在某些种族中更为常见，这是瘢痕疙瘩的遗传基础 编队仍不得而知。我们假设SDF1的增加促进了人类病理的形成 伤痕累累。事实上，人类瘢痕疙瘩组织中含有更多的SDF1。我们建议识别单核苷酸 瘢痕疙瘩易感患者和对照组SDF1基因的多态性。已确定的多态将是 介绍并在体外人体皮肤有机系统中进行了功能测试。这项建议旨在 了解SDF1如何调节伤口愈合和组织再生，并破译 人类病理性疤痕的形成。

Abstract/Summary Cutaneous wounds create significant health problems for Veterans, including wartime trauma, diabetic foot ulcers, pressure ulcers, and pathological scar formation. We aim to devise novel methods to stimulate self- repair mechanisms and to promote scar-less wound healing/full tissue regeneration in humans. We use a combination of loss-of-function mouse genetics, parabiosis (where the circulatory systems of two mice are surgically connected), mass cytometry, flow cytometry, genomics, lineage tracing, and molecular biology to study ear tissue regeneration in mice. Our prior work and current preliminary data demonstrate that in two different physiologic contexts, skin-secreted SDF1 regulates the switch between scar formation and tissue regeneration. In Aim 1, we will study how SDF1 promotes scarring and fibrosis. The canonical receptor for SDF1 is CXCR4. After injury, we hypothesize that skin-secreted SDF1 recruits CXCR4+ immune cells, which produce paracrine factors that induce fibroblasts to form fibrous tissue and scar. Recruited cell types will be defined and functionally tested. In Aim 2, we translate our findings directly into humans. While pathologic scar formation (keloids and hypertrophic scars) is more common in certain ethnicities, the genetic basis of keloid formation remains unknown. We hypothesize that increased SDF1 promotes formation of human pathologic scars. Indeed, human keloid tissue contains higher amounts of SDF1. We propose to identify single nucleotide polymorphisms in the SDF1 gene of keloid-prone and control patients. Identified polymorphisms will be introduced and functionally tested in an ex vivo human skin organoid system. This proposal seeks to understand how SDF1 regulates wound healing and tissue regeneration and to decipher the genetic basis for pathologic scar formation in humans.