Role of the FAAH-OUT locus in cutaneous wound healing

研究综述 该提案将研究一名69岁女性的不同寻常的表型，她表现出异常的 加速皮肤伤口愈合，最大限度减少疤痕。基因组测序显示，她 表型是由脂肪酸醛水解酶下游~8kb的缺失引起的 (FAAH)基因，导致名为FAAH Out的长非编码RNA(LncRNA)基因的丢失。 本提案的目标是了解FAAH删除如何导致加速 伤口愈合。在美国，慢性伤口每年的医疗负担超过25美元 10亿美元，并随着人口老龄化而继续上升。迫切需要改进 了解皮肤伤口愈合的生物学过程并创新 治疗。在第一个目标中，我们将从研究对象出发研究正常皮肤组织和损伤皮肤组织 使用空间转录、原位杂交和异种移植皮肤修复模型来理解 FAAHOUT基因如何调控伤口愈合。在第二个目标中，我们将阐明FAAH 基因互作组学以了解其分子机制。通过研究一种罕见的基因 伤口愈合显著增强的个体的等位基因，这一提议旨在产生 对lncRNAs在伤口修复中作用的新见解，并发现新的人类验证靶点 治疗皮肤伤口。

RESEARCH SUMMARY The proposal will study the unusual phenotype of a 69-year-old woman who displays exceptionally accelerated skin wound healing with minimal scarring. Genome sequencing revealed that her phenotype is caused by an ~8 kb deletion downstream of the fatty acid aldehyde hydrolase (FAAH) gene that results in the loss of a long noncoding RNA (lncRNA) gene named FAAH OUT. The goal of this proposal is to understand how the FAAH OUT deletion results in accelerated wound healing. In the United States, the annual medical burden of chronic wounds exceeds $25 billion and continues to rise with the aging population. There is a critical need to improve understanding of the biological processes underlying skin wound healing and to innovate new therapies. In the first aim, we will study normal and wounded skin tissue from the study subject using spatial transcriptomics, in situ hybridization, and xenograft skin repair models to understand how the FAAH OUT locus regulates wound healing. In the second aim, we will elucidate the FAAH OUT genetic interactome to gain insight to its molecular mechanisms. By studying a rare genetic allele of an individual with markedly enhanced wound healing, this proposal aims to generate novel insight to the role of lncRNAs in wound repair and discover new human-validated targets to treat cutaneous wounds.